| 1. |
- Carlsson, Axel C, et al.
(författare)
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Soluble tumor necrosis factor receptor 1 is associated with glomerular filtration rate progression and incidence of chronic kidney disease in two community-based cohorts of elderly individuals
- 2015
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Ingår i: CardioRenal Medicine. - : S. Karger AG. - 1664-3828 .- 1664-5502. ; 5:4, s. 278-288
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Tidskriftsartikel (refereegranskat)abstract
- Objective: We aimed to explore and validate the longitudinal associations between soluble tumor necrosis factor receptor 1 (sTNFR1), glomerular filtration rate (GFR) progression, and chronic kidney disease (CKD) incidence in two independent community-based cohorts of elderly individuals with prespecified subgroup analyses in individuals without prevalent diabetes.Research design and methods: Two community-based cohorts of elderly individuals were used with 5-year follow-up data on estimated GFR: the Uppsala Longitudinal Study of Adult Men (ULSAM; n = 437 men; mean age: 78 years) and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; n = 703; mean age: 70 years; 51% women). GFR categories were defined as >= 60, 30-60, and <30 ml/min/1.73 m(2).Results: In longitudinal multivariable logistic regression models adjusted for inflammatory markers and established cardiovascular risk factors, higher serum sTNFR1 was significantly associated with an increased risk to progress to a lower GFR category in both ULSAM and PIVUS [odds ratio (OR) per standard deviation (SD) increase 1.28 (95% CI 1.03-1.60) and OR 1.56 (95% CI 1.30-1.87), respectively]. Also, in subgroup analyses in individuals with a GFR >= 60 ml/min/1.73 m(2) at baseline, higher sTNFRs were associated with incident CKD after 5 years in both cohorts [ULSAM: OR per SD increase 1.49 (95% CI 1.16-1.9) and PIVUS: OR 1.84 (95% CI 1.50-2.26)]. Associations were similar in individuals without diabetes.Conclusions: Higher circulating sTNFR1 independently predicts the progression to a worse GFR category and CKD incidence in elderly individuals even in the absence of diabetes. Further studies are warranted to investigate the underlying mechanisms, and to evaluate the clinical relevance of our findings.
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| 2. |
- Friederich, Malou, et al.
(författare)
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Diabetes-induced up-regulation of uncoupling protein-2 results in increased mitochondrial uncoupling in kidney proximal tubular cells
- 2008
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Ingår i: Biochimica et Biophysica Acta. - : Elsevier BV. - 0006-3002 .- 1878-2434 .- 0005-2728. ; 1777:7-8, s. 935-940
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Tidskriftsartikel (refereegranskat)abstract
- We have previously reported increased O(2) consumption unrelated to active transport by tubular cells and up-regulated mitochondrial uncoupling protein (UCP)-2 expressions in diabetic kidneys. It is presently unknown if the increased UCP-2 levels in the diabetic kidney results in mitochondrial uncoupling and increased O(2) consumption, which we therefore investigated in this study. The presence of UCP-2 in proximal tubular cells was confirmed by immunohistochemistry and found to be increased (western blot) in homogenized tissue and isolated mitochondria from kidney cortex of diabetic rats. Isolated proximal tubular cells had increased total and ouabain-insensitive O(2) consumption compared to controls. Isolated mitochondria from diabetic animals displayed increased glutamate-stimulated O(2) consumption (in the absence of ADP and during inhibition of the ATP-synthase by oligomycin) compared to controls. Guanosine diphosphate, an UCP inhibitor, and bovine serum albumin which removes fatty acids that are essential for UCP-2 uncoupling activity, independently prevented the increased glutamate-stimulated O(2) consumption in mitochondria from diabetic animals. In conclusion, diabetic rats have increased mitochondrial UCP-2 expression in renal proximal tubular cells, which results in mitochondrial uncoupling and increased O(2) consumption. This mechanism may be protective against diabetes-induced oxidative stress, but will increase O(2) usage. The subsequently reduced O(2) availability may contribute to diabetes-induced progressive kidney damage.
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| 3. |
- Friederich, Malou, 1983-, et al.
(författare)
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Identification and distribution of uncoupling protein isoforms in the normal and diabetic rat kidney
- 2009
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Ingår i: Advances in Experimental Medicine and Biology. - New York : Springer. - 0065-2598 .- 2214-8019. - 9780387859972 ; 645, s. 205-212
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Tidskriftsartikel (refereegranskat)abstract
- Uncoupling protein (UCP)-2 and -3 are ubiquitously expressed throughout the body but there is currently no information regarding the expression and distribution of the different UCP isoforms in the kidney. Due to the known cross-reactivity of the antibodies presently available for detection of UCP-2 and -3 proteins, we measured the mRNA expression of UCP-1, -2 and -3 in the rat kidney in order to detect the kidney-specific UCP isoforms. Thereafter, we determined the intrarenal distribution of the detected UCP isoforms using immunohistochemistry. Thereafter, we compared the protein levels in control and streptozotocin-induced diabetic rats using Western blot. Expressions of the UCP isoforms were also performed in brown adipose tissue and heart as positive controls for UCP-1 and 3, respectively. UCP-2 mRNA was the only isoform detected in the kidney. UCP-2 protein expression in the kidney cortex was localized to proximal tubular cells, but not glomerulus or distal nephron. In the medulla, UCP-2 was localized to cells of the medullary thick ascending loop of Henle, but not to the vasculature or parts of the nephron located in the inner medulla. Western blot showed that diabetic kidneys have about 2.5-fold higher UCP-2 levels compared to controls. In conclusion, UCP-2 is the only isoform detectable in the kidney and UCP-2 protein can be detected in proximal tubular cells and cells of the medullary thick ascending loop of Henle. Furthermore, diabetic rats have increased UCP-2 levels compared to controls, but the mechanisms underlying this increase and its consequences warrants further studies.
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| 4. |
- Friederich Persson, Malou, et al.
(författare)
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Acute knockdown of uncoupling protein-2 increases mitochondria uncoupling via the adenine nucleotide transporter and decreases oxidative stress in diabetic kidneys
- 2012
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:7, s. e39635-
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Tidskriftsartikel (refereegranskat)abstract
- Increased O2 metabolism resulting in chronic hypoxia is common in models of endstage renal disease. Mitochondrial uncoupling increases O2 consumption but the ensuing reduction in mitochondrial membrane potential may limit excessive oxidative stress. The present study addressed the hypothesis that mitochondrial uncoupling regulates mitochondria function and oxidative stress in the diabetic kidney. Isolated mitochondria from kidney cortex of control and streptozotocin-induced diabetic rats were studied before and after siRNA knockdown of uncoupling protein-2 (UCP-2). Diabetes resulted in increased UCP-2 protein expression and UCP-2-mediated uncoupling, but normal mitochondria membrane potential. This uncoupling was inhibited by GDP, which also increased the membrane potential. siRNA reduced UCP-2 protein expression in controls and diabetics (−30–50%), but paradoxically further increased uncoupling and markedly reduced the membrane potential. This siRNA mediated uncoupling was unaffected by GDP but was blocked by ADP and carboxyatractylate (CAT). Mitochondria membrane potential after UCP-2 siRNA was unaffected by GDP but increased by CAT. This demonstrated that further increased mitochondria uncoupling after siRNA towards UCP-2 is mediated through the adenine nucleotide transporter (ANT). The increased oxidative stress in the diabetic kidney, manifested as increased thiobarbituric acids, was reduced by knocking down UCP-2 whereas whole-body oxidative stress, manifested as increased circulating malondialdehyde, remained unaffected. All parameters investigated were unaffected by scrambled siRNA. In conclusion, mitochondrial uncoupling via UCP-2 regulates mitochondria membrane potential in diabetes. However, blockade of the diabetes-induced upregulation of UCP- 2 results in excessive uncoupling and reduced oxidative stress in the kidney via activation of ANT.
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| 5. |
- Friederich-Persson, Malou, et al.
(författare)
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Acute Knockdown of Uncoupling Protein-2 Increases Uncoupling via the Adenine Nucleotide Transporter and Decreases Oxidative Stress in Diabetic Kidneys
- 2012
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 7:7, s. e39635-
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Tidskriftsartikel (refereegranskat)abstract
- Increased O(2) metabolism resulting in chronic hypoxia is common in models of endstage renal disease. Mitochondrial uncoupling increases O(2) consumption but the ensuing reduction in mitochondrial membrane potential may limit excessive oxidative stress. The present study addressed the hypothesis that mitochondrial uncoupling regulates mitochondria function and oxidative stress in the diabetic kidney. Isolated mitochondria from kidney cortex of control and streptozotocin-induced diabetic rats were studied before and after siRNA knockdown of uncoupling protein-2 (UCP-2). Diabetes resulted in increased UCP-2 protein expression and UCP-2-mediated uncoupling, but normal mitochondria membrane potential. This uncoupling was inhibited by GDP, which also increased the membrane potential. siRNA reduced UCP-2 protein expression in controls and diabetics (-30-50%), but paradoxically further increased uncoupling and markedly reduced the membrane potential. This siRNA mediated uncoupling was unaffected by GDP but was blocked by ADP and carboxyatractylate (CAT). Mitochondria membrane potential after UCP-2 siRNA was unaffected by GDP but increased by CAT. This demonstrated that further increased mitochondria uncoupling after siRNA towards UCP-2 is mediated through the adenine nucleotide transporter (ANT). The increased oxidative stress in the diabetic kidney, manifested as increased thiobarbituric acids, was reduced by knocking down UCP-2 whereas whole-body oxidative stress, manifested as increased circulating malondialdehyde, remained unaffected. All parameters investigated were unaffected by scrambled siRNA. In conclusion, mitochondrial uncoupling via UCP-2 regulates mitochondria membrane potential in diabetes. However, blockade of the diabetes-induced upregulation of UCP- 2 results in excessive uncoupling and reduced oxidative stress in the kidney via activation of ANT.
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| 6. |
- Friederich-Persson, Malou, et al.
(författare)
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Angiotensin II Reduces Transport-Dependent Oxygen Consumption but Increases Transport-Independent Oxygen Consumption in Immortalized Mouse Proximal Tubular Cells
- 2014
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Ingår i: Advances in Experimental Medicine and Biology. - New York, NY : Springer New York. - 0065-2598 .- 2214-8019. - 9781493906208 - 9781493905836 ; 812, s. 157-163
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Tidskriftsartikel (refereegranskat)abstract
- Oxidative stress is closely associated with renal dysfunction following diabetes and hypertension. Angiotensin II (Ang II) can activate the NADPH-oxidase, increasing oxidative stress that is thought to blunt proximal tubular electrolyte transport and thereby oxygen consumption (QO(2)). We investigated the effect of Ang II on QO(2) in immortalized mouse proximal tubular cells over-expressing the NADPH oxidase subunit p22(phox); a model of increased oxidative stress. Cultured cells were exposed to either Ang II or H2O2 for 48 h. QO(2) was determined during baseline (113 mmol/l NaCl; transport-dependent QO(2)) and during sodium-free conditions (transport-independent QO(2)). Ang II reduced transport-dependent QO(2) in wild-types, but not in p22(phox) which also displayed increased QO(2) at baseline. Transport-independent QO(2) was increased in p22(phox) and Ang II had no additional effect, whereas it increased QO(2) in wild-type. Addition of H2O2 reduced transport-dependent QO(2) in wild-types, but not in p22(phox). Transport-independent QO(2) was unaffected by H2O2. The similar effects of Ang II and H2O2 to reduce transport-dependent QO(2) suggest a direct regulatory role of oxidative stress. In accordance, the transport-dependent QO(2) was reduced in p22(phox) already during baseline. The effects of Ang II on transport-independent QO(2) was not replicated by H2O2, indicating direct regulation via Ang II-receptors independently of oxidative stress. However, the Ang II effect was absent in p22(phox), suggesting that oxidative stress also modulates normal Ang II signaling. In conclusion, Ang II affects both transport-dependent and transport-independent QO(2) in proximal tubular cells and may be an important pathway modulating renal QO(2).
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| 7. |
- Friederich-Persson, Malou, et al.
(författare)
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Increased kidney metabolism as a pathway to kidney tissue hypoxia and damage : effects of triiodothyronine and dinitrophenol in normoglycemic rats.
- 2013
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Ingår i: Advances in Experimental Medicine and Biology. - New York, NY : Springer-Verlag New York. - 0065-2598 .- 2214-8019. - 9781461474111 - 9781461472568 ; 789, s. 9-14
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Tidskriftsartikel (refereegranskat)abstract
- Intrarenal tissue hypoxia is an acknowledged common pathway to end-stage renal disease in clinically common conditions associated with development of chronic kidney disease, such as diabetes and hypertension. In diabetic kidneys, increased oxygen metabolism mediated by mitochondrial uncoupling results in decreased kidney oxygen tension (PO2) and contributes to the development of diabetic nephropathy. The present study investigated whether increased intrarenal oxygen metabolism per se can cause intrarenal tissue hypoxia and kidney damage, independently of confounding factors such as hyperglycemia and oxidative stress. Male Sprague-Dawley rats were untreated or treated with either triiodothyronine (T3, 10 g/kg bw/day, subcutaneously for 10 days) or the mitochondria uncoupler dinitrophenol (DNP, 30 mg/kg bw/day, oral gavage for 14 days), after which in vivo kidney function was evaluated in terms of glomerular filtration rate (GFR, inulin clearance), renal blood flow (RBF, Transonic, PAH clearance), cortical PO2 (Clark-type electrodes), kidney oxygen consumption (QO2), and proteinuria. Administration of both T3 and DNP increased kidney QO2 and decreased PO2 which resulted in proteinuria. However, GFR and RBF were unaltered by either treatment. The present study demonstrates that increased kidney metabolism per se can cause intrarenal tissue hypoxia which results in proteinuria. Increased kidney QO2 and concomitantly reduced PO2 may therefore be a mechanism for the development of chronic kidney disease and progression to end-stage renal disease.
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| 8. |
- Hultström, Michael, 1978-, et al.
(författare)
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Intradermal insulin delivery : A promising future for diabetes management
- 2014
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Ingår i: Journal of Diabetes Science and Technology. - : SAGE Publications. - 1932-2968. ; 8:3, s. 453-457
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Tidskriftsartikel (refereegranskat)abstract
- The incidence of insulinopenic diabetes mellitus is constantly increasing, and in addition, approximately a third of all hyperinsulinemic diabetic patients develop insulinopenia. Optimal glycemic control is essential to minimize the risk for diabetes-induced complications, but the majority of diabetic patients fail to achieve proper long-term glucose levels even in clinical trials, and even more so in clinical practice. Compliance with a treatment regimen is likely to be higher if the procedure is simple, painless, and discreet. Thus, insulin has been suggested for nasal, gastrointestinal, and inhalation therapy, but so far with considerable downsides in effect, side effects, or patient acceptance. The stratum corneum is the main barrier preventing convenient drug administration without the drawbacks of subcutaneous injections. Recently, devices with miniaturized needles have been developed that combine the simplicity and discretion of patch-based treatments, but with the potential of peptide and protein administration. As this review describes, initial comparisons with subcutaneous administration now suggest microneedle patches for active insulin delivery are efficient in maintaining glycemic control. Hollow microneedle technology could also prove to be efficient in systemic as well as local delivery of other macromolecular drugs, such as vaccines.
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| 9. |
- Lindahl, Emma, et al.
(författare)
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Early transcriptional regulation by C-peptide in freshly isolated rat proximal tubular cells
- 2011
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Ingår i: Diabetes/Metabolism Research Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 27:7, s. 697-704
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Clinical studies have shown that proinsulin C-peptide exerts renoprotective effects in type 1 diabetes, although the underlying mechanisms are poorly understood. As C-peptide has been shown to induce several intracellular events and to localize to nuclei, we aimed to determine whether gene transcription is affected in proximal tubular kidney cells, and if so, whether genes with altered transcription include those related to protective mechanisms. METHODS: The effect of C-peptide incubation (2h) on gene expression was investigated in freshly isolated proximal tubular cells from streptozotocin-diabetic Sprague-Dawley rats using global gene expression profiling and RT-qPCR. Protein expression was assayed using western blotting. Different bioinformatic strategies were employed. RESULTS: Gene transcription profiling demonstrated differential transcription of 492 genes (p<0.01) after 2h of C-peptide exposure, with the majority of these genes repressed (83%). RT-qPCR validation supported a trend of several GPCR's being activated, and certain transcription factors to be repressed. Also, C-peptide repressed the transcription of genes associated with pathways of circulatory and inflammatory diseases. CONCLUSIONS: This study shows that C-peptide exerts early effects on gene transcription in proximal tubular cells. The findings also bring further knowledge to the renoprotective mechanisms of C-peptide in type I diabetes, and supports a transcriptional activity for C-peptide. It is suggested that C-peptide may play a regulatory role in the gene expression of proximal tubular cells.
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| 10. |
- Nordquist, Lina, et al.
(författare)
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Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy
- 2015
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Ingår i: Journal of the American Society of Nephrology. - : American Society of Nephrology. - 1046-6673 .- 1533-3450. ; 26:2, s. 328-338
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Tidskriftsartikel (refereegranskat)abstract
- Hyperglycemia results in increased oxygen consumption and decreased oxygen tension in the kidney. We tested the hypothesis that activation of hypoxia-inducible factors (HIFs) protects against diabetes-induced alterations in oxygen metabolism and kidney function. Experimental groups consisted of control and streptozotocin-induced diabetic rats treated with or without chronic cobalt chloride to activate HIFs. We elucidated the involvement of oxidative stress by studying the effects of acute administration of the superoxide dismutase mimetic tempol. Compared with controls, diabetic rats displayed tissue hypoxia throughout the kidney, glonnerular hyperfiltration, increased oxygen consumption, increased total mitochondrial leak respiration, and decreased tubular sodium transport efficiency. Diabetic kidneys showed proteinuria and tubulointerstitial damage. Cobalt chloride activated HIFs, prevented the diabetes-induced alterations in oxygen metabolism, mitochondrial leak respiration, and kidney function, and reduced proteinuria and tubulointerstitial damage. The beneficial effects of tempol were less pronounced after activation of HIFs, indicating improved oxidative stress status. In conclusion, activation of HIFs prevents diabetes-induced alteration in kidney oxygen metabolism by normalizing glomerular filtration, which reduces tubular electrolyte load, preventing mitochondrial leak respiration and improving tubular transport efficiency. These improvements could be related to reduced oxidative stress and account for the reduced proteinuria and tubulointerstitial damage. Thus, pharnnacologic activation of the HIF system may prevent development of diabetic nephropathy.
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| 11. |
- Nordquist, Lina, 1977-, et al.
(författare)
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C-Peptide : The missing link in diabetic nephropathy?
- 2009
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Ingår i: The review of diabetic studies : RDS. - 1614-0575. ; 6:3, s. 203-210
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Tidskriftsartikel (refereegranskat)abstract
- Proinsulin C-peptide has been found to exert beneficial effects in many tissues affected by diabetic microvascular complications, including the kidneys. Glomerular hyperfiltration and microalbuminuria are early markers of diabetic nephropathy. C-peptide at physiological concentrations effectively reduces diabetes-induced glomerular hyperfiltration via constriction of the afferent arteriole, dilation of the efferent arteriole, and inhibition of tubular reabsorption in experimental models of type 1 diabetes. The glomerular hypertrophy and mesangial matrix expansion seen in early diabetes can be reduced or prevented by C-peptide administration, possibly via interference with TGF-beta1 and TNFalpha signaling. Several of C-peptide's reno-protective effects have been confirmed in human studies; reduced glomerular hyperfiltration and diminished urinary albumin excretion have been documented in type 1 diabetes patients receiving replacement doses of C-peptide for periods of up to 3 months. In this review, we critically summarize the current state of knowledge regarding C-peptide's renal effects, and discuss possible mechanisms of its beneficial effects in diabetic nephropathy.
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| 12. |
- Nordquist, Lina, 1977-, et al.
(författare)
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C-peptide constricts pancreatic islet arterioles in diabetic, but not normoglycaemic mice
- 2008
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Ingår i: Diabetes/Metabolism Research Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 24:2, s. 165-168
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Pancreatic islet blood flow is regulated separately from that of the exocrine pancreas, and a consistent finding during impaired glucose tolerance is an increased blood perfusion. The aim of the present study was to investigate whether C-peptide affects pancreatic islet arterioles in normal and diabetic mice. MATERIALS AND METHODS: Control and diabetic C57-Bl mice were studied after 2 weeks of alloxan-induced diabetes. Islet arterioles were dissected and microperfused with Dulbecco's modified Eagle medium (DMEM) solution. The effect of luminal application of mouse C-peptide was investigated. RESULTS: C-peptide reduced the diameter of islet arterioles from diabetic mice (-10+/-4%, P<0.05) compared to base-line values, whilst arterioles from normoglycaemic animals did not respond to C-peptide (P=0.2). CONCLUSION: These findings suggest a role for C-peptide in the regulation of islet blood flow, especially during conditions with impaired glucose tolerance.
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| 13. |
- Nordquist, Lina, 1977-
(författare)
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Dabbling in science journalism
- 2006
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Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 439:7077, s. 760-760
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Recension (populärvet., debatt m.m.)
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| 14. |
- Nordquist, Lina, 1977-, et al.
(författare)
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Diabetes-induced alterations in renal medullary microcirculation and metabolism
- 2007
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Ingår i: Current diabetes reviews. - 1573-3998. ; 3:1, s. 53-65
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Forskningsöversikt (refereegranskat)abstract
- Diabetes-induced renal complications, i.e. diabetes nephropathy, are a major cause of morbidity and mortality. The exact mechanisms mediating the negative influence of hyperglycemia on renal function are unclear, although several hypotheses have been postulated. Cellular mechanisms include glucose-induced excessive formation of reactive oxygen species, increased glucose flux through polyol pathway and pentose phosphate shunt, formation of advanced glycation end-products and activation of protein kinase C and NADPH oxidase. However, the renal effects in vivo of each and every one of these mechanisms are less clear, although recent studies have shown several major alterations predominantly in the renal medulla as a result of sustained hyperglycemia. Already during normal conditions, the renal medulla has a remarkably low oxygen tension (PO2) and a high degree of non-oxygen dependent energy metabolism. Alterations in either blood perfusion or oxygen delivery to the medullary region will have significant effects on both regional metabolism and total kidney function. Recently, sustained hyperglycemia has been shown to induce a pronounced reduction in preferentially renal medullary PO2. This review will present the current knowledge of diabetes-induced alterations in renal medullary metabolism and function, but also discuss future targets for prevention of diabetic nephropathy.
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| 15. |
- Nordquist, Lina, 1977-, et al.
(författare)
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Effects of proinsulin C-peptide on oxygen transport, uptake and utilization in insulinopenic diabetic subjects : a review
- 2009
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Ingår i: Advances in Experimental Medicine and Biology. - New York : Springer US. - 0065-2598 .- 2214-8019. - 9780387859972 - 9780387859989 ; 645, s. 193-198
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Tidskriftsartikel (refereegranskat)abstract
- Exogenous C-peptide administration has beneficial effects in many of the tissues commonly affected by diabetic complications. Diabetes-induced circulatory impairments such as decreased blood flow are prevented by C-peptide, possibly via Ca2+-mediated effects on nitric oxide release. C-peptide also improves diabetes-induced erythrocyte deformability, which likely improves oxygen availability and uptake in affected tissues. Furthermore, C-peptide prevents diabetic neuropathy via improvements of endoneural blood flow and by preventing axonal swelling. In the kidney, C-peptide normalizes the diabetes-induced increase in oxygen consumption via inhibition of the Na+/K+-ATPase. Surprisingly, C-peptide has also been shown to prevent complications in patients with type II diabetes. Taken together, these results may indicate that C-peptide treatment has the potential to reduce the prevalence of diabetic complications. In this paper, the current knowledge regarding these beneficial effects of C-peptide administered to diabetic subjects will be reviewed briefly.
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| 16. |
- Nordquist, Lina, et al.
(författare)
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Hypoxia in the diabetic kidney is independent of advanced glycation end-products.
- 2013
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Ingår i: Advances in Experimental Medicine and Biology. - New York, NY : Kluwer Academic Publishers. - 0065-2598 .- 2214-8019. ; 765, s. 185-193
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Tidskriftsartikel (refereegranskat)abstract
- Sustained hyperglycemia is closely associated with increased risk to develop nephropathy. We have previously reported alterations in the intrarenal oxygen metabolism already after the early onset of diabetes. Furthermore, formation of advanced glycation end-products (AGE) is postulated as a major contributor to diabetic nephropathy. We therefore investigated the possible relationship between altered oxygen metabolism and AGE in diabetic kidneys.Normoglycemic and streptozotocin-diabetic rats with and without chronic treatment with aminoguanidine (AGE inhibitor; 600 mg/kg bw/24 h in drinking water) or L-N(6)-(1-Iminoethyl)lysine (L-NIL, iNOS inhibitor, 1 mg/kg bw/24 h in drinking water) were studied 2 weeks after induction of diabetes. Glomerular filtration rate (GFR) was estimated by inulin clearance, oxygen tension (pO(2)) and interstitial pH by microelectrodes and regional renal blood flow (RBF) by laser-Doppler. Histological changes were evaluated on fixed tissue.Glomerular hyperfiltration was unaffected by aminoguanidine, whereas L-NIL normalized GFR in diabetic rats. pO(2) and interstitial pH, but not RBF, were lower in both kidney cortex and medulla compared to control rats, but was unaffected by both chronic treatments. Urinary protein excretion was higher in diabetic rats and unaffected by L-NIL, whereas aminoguanidine paradoxically increased this parameter. Damage scores were similar in all groups.In conclusion, diabetes-induced alterations in intrarenal oxygen metabolism are independent of the AGE pathway, and precede any morphological changes. These findings highlight the early stage of diabetes as being a metabolic disorder also in the kidney.
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| 17. |
- Nordquist, Lina, 1977-, et al.
(författare)
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Improvement of insulin response in the streptozotocin model of insulin-dependent diabetes mellitus. : Insulin response with and without a long-acting insulin treatment
- 2009
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Ingår i: Animal. - : Cambridge university press. - 1751-7311 .- 1751-732X. ; 3:5, s. 685-689
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Tidskriftsartikel (refereegranskat)abstract
- Streptozotocin-induced diabetes mellitus (STZ-DM) in rats is a model of type 1 diabetes, which is commonly used to study diabetes, but differs from human diabetic pathophysiology in its insulin resistance, An STZ-DM rat can be administered five times the dose of insulin compared to that of a diabetic patient. Thus, attaining normoglycaemia in STZ-DM rats with insulin injections is complicated, and it involves an obvious risk of overdosing before getting a response. This study was designed to investigate whether suboptimal treatment with long-acting insulin restores insulin sensitivity in the STZ-DM rat, and thus an approach to more closely mimic the human condition. Male Sprague-Dawley rats were made diabetic by means of a single intravenous injection of STZ (55 mg/kg body weight (BW)), resulting in an increase in blood glucose (BG) from 6.5 +/- 0.2 to 22.5 +/- 1.0 mmol/l (P <= 0.05) within 24h. After treating the STZ-DM rats with vehicle for 14 days, BG was 26.1 +/- 1.1 mmol/l, and the response to a single injection of fast-acting insulin (Humalog, 5 IE/kg BW) was a 23% reduction in BG. Thereafter, the rats were treated daily with a suboptimal dose of long-acting insulin for a total of 7 days (Insulatard, 5 IE/kg per day), which resulted in a BG level of 19.4 +/- 2.7. The response to fast-acting insulin after the suboptimal treatment was a 61% reduction in BG. Thereafter, the animals were vehicle-treated for another 7 days, which resulted in a response to fast-acting insulin similar to the initial values (-34%). Furthermore, the group treated with suboptimal doses of long-acting insulin had a longer duration of the reduction in BG (150 min, as opposed to 90 min in the vehicle-treated groups). We conclude that the development of a decreased insulin response occurs rapidly within the first 2 weeks after the onset of diabetes in STZ-DM rats. This leads to a brief and significantly reduced decrease in BG when tast-acting insulin is administered, The insulin response is increased by treatment with suboptimal doses of long-acting insulin, but rapidly decreases again when treatment is withdrawn. Regular administration of suboptimal insulin doses may provide an approach to eliminate the effects of a lowered insulin response.
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| 18. |
- Nordquist, Lina, 1977-
(författare)
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Novel Approaches to Treatment and Prevention of Diabetic Nephropathy
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Several studies have reported beneficial effects of C-peptide supplementation in diabetic patients and animal models of insulinopenic diabetes. However, it is also established that good glycemic control is essential to minimize the risk of diabetes-induced complications. This thesis investigates potential mechanisms for the beneficial effect of C-peptide on glomerular hyperfiltration, and a novel, painless route of insulin administration. The results demonstrate that both C-peptide and its C-terminal penta-peptide sequence reduce the diabetes-induced glomerular hyperfiltration within an hour. The results also indicate that C-peptide possibly reduces diabetes-induced hyperfiltration via three different mechanisms: 1. Constriction of the afferent arteriole was demonstrated on isolated vessels from diabetic mice. 2. A net dilation of the efferent arteriole was evident in vivo. 3. Inhibition of the Na+/K+-ATPase was demonstrated in vivo in diabetic rats as well as in vitro on isolated proximal tubular cells from diabetic rats. All these mechanisms are known regulators of the net glomerular filtration pressure. The last part of this thesis demonstrates that intradermal administration with a newly developed patch-like microneedle device results in similar insulin concentration compared to standard subcutaneous delivery. These findings provide an insight for the beneficial effects of C-peptide on diabetic kidney function, and shows that this effect can be achieved by infusion of the C-terminal penta-peptide sequence alone. This thesis also presents a novel, painless alternative to insulin injections that is controllable, requires minimal training, and therefore presents several advantages compared to current standard therapy.
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| 19. |
- Nordquist, Lina, 1977-, et al.
(författare)
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Novel microneedle patches for active insulin delivery are efficient in maintaining glycaemic control : an initial comparison with subcutaneous administration
- 2007
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Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 24:7, s. 1381-1388
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Good glycaemic control is essential to minimize the risk for diabetes-induced complications. Also, compliance is likely to be higher if the procedure is simple and painless. This study was designed to validate painless intradermal delivery via a patch-like microneedle array. MATERIALS AND METHODS: Diabetes was induced by an intravenous injection of streptozotocin (50 mg/kg bw) in adult male Sprague Dawley rats. Plasma insulin and blood glucose were measured before, during and after subcutaneous or intradermal (microneedles) infusion of insulin (0.2 IU/h) under Inactin-anaesthesia. RESULTS: Before insulin administration, all animals displayed a pronounced hyperglycaemia (19 +/- 1 mM; 359 mg/dl). Administration of insulin resulted in a reduced plasma glucose independently of administration route (subcutaneous 7.5 +/- 4.2, n = 9, and intradermal 11 +/- 1.8, n = 9 after 240 min), but with less errors of the mean in the intradermal group. In the intradermal group, plasma insulin was increased in all latter measurements (72 +/- 22, 81 +/- 34, and 87 +/- 20 microIU/ml), as compared to the first measurement (26 +/- 13). In the subcutaneous group, plasma insulin was elevated during the last measurement (to 154 +/- 3.5 microIU/ml from 21 +/- 18). CONCLUSION: This study presents a novel possibility of insulin delivery that is controllable and requires minimal training. This treatment strategy could improve compliance, and thus be beneficial for patients' glycaemic control.
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| 20. |
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| 21. |
- Nordquist, Lina, 1977-, et al.
(författare)
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Proinsulin C-peptide : friend or foe in the development of diabetes-associated complications?
- 2008
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Ingår i: Vascular health and risk management. - 1178-2048. ; 4:6, s. 1283-1288
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Forskningsöversikt (övrigt vetenskapligt/konstnärligt)abstract
- The proinsulin connecting peptide, C-peptide, is a cleavage product of insulin synthesis that is co-secreted with insulin by pancreatic beta-cells following glucose stimulation. Recombinant insulin, used in the treatment of diabetes, lacks C-peptide and preclinical and clinical studies suggest that lack of C-peptide may exacerbate diabetes-associated complications. In accordance with this, several studies suggest that C-peptide has beneficial effects in a number of diabetes-associated complications. C-peptide has been shown to prevent diabetic neuropathy by improving endoneural blood flow, preventing neuronal apoptosis and by preventing axonal swelling. In the vascular system, C-peptide has been shown to prevent vascular dysfunction in diabetic rats, and to possess anti-proliferative effects on vascular smooth muscle cells, which may prevent atherosclerosis. However, C-peptide depositions have been found in arteriosclerotic lesions of patients with hyperinsulinemic diabetes and C-peptide has been shown to induce pro-inflammatory mediators, such as nuclear factor kappa B, inducible nitric oxide synthase, and cyclooxygenase-2, indicating that C-peptide treatment could be associated with side-effects that may accelerate the development of diabetes-associated complications. This review provides a brief summary of recent research in the field and discusses potential beneficial and detrimental effects of C-peptide supplementation.
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| 22. |
- Nordquist, Lina, 1977-, et al.
(författare)
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Proinsulin C-peptide constricts glomerular afferent arterioles in diabetic mice : A potential renoprotective mechanism
- 2008
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Ingår i: American Journal of Physiology. Regulatory Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 294:3, s. R836-R841
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: an increased glomerular filtration rate (GFR) has been postulated as a potential mechanism involved in the progression of diabetic nephropathy. Studies suggest that C-peptide exerts a renoprotective effect on diabetes. The peptide decreases hyperfiltration in patients with type 1 diabetes, as well as in diabetic animal models. In this study, we investigated whether C-peptide causes a change in arteriolar diameter. RESEARCH DESIGN AND METHODS: C57-Bl mice were made diabetic by means of a single intravenous injection of alloxan 2 wk prior to the experiment. Age-matched normoglycemic mice served as controls. Afferent arterioles, intact with the glomeruli, were dissected and microperfused. The effect of luminal application of C-peptide, compared with scrambled C-peptide or vehicle, was investigated. The effect of the Rho-kinase inhibitor Y-27632 was also investigated. RESULTS: C-peptide constricted afferent arterioles in diabetic mice by -27% compared with the control value. Normoglycemic arterioles administered C-peptide displayed a delayed and minute response (-4%). Scrambled C-peptide or vehicle administration, whether administered to hyperglycemic or normoglycemic mice, did not induce any effect. Addition of Y-27632 abolished the effect of C-peptide. CONCLUSION: C-peptide induces constriction of afferent arterioles in diabetic mice. This can reduce enhanced GFR and may be one of the mechanisms in the renoprotective action of C-peptide in diabetes.
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| 23. |
- Nordquist, Lina, 1977-, et al.
(författare)
-
Proinsulin C-peptide prevents type-1 diabetes-induced decrease of renal Na(+)-K(+)-ATPase alpha1-subunit in rats
- 2010
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Ingår i: Diabetes/Metabolism Research Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 26:3, s. 193-199
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: C-peptide reduces renal damage in diabetic patients and experimental animal models. In vitro studies suggest that the renal effects of C-peptide may, in part, be explained by stimulation of Na(+)/K(+)-ATPase activity. However, the responses of Na(+)/K(+)-ATPase expression in the kidney of diabetic animals to C-peptide administration remain unclear. The aim of this study was to clarify the responses. METHODS: Type 1 diabetic rats were produced by injecting streptozotocin (STZ), and some of the rats were treated with either C-peptide or insulin by the aid of an osmotic pump for 1 week. The mRNA expression and immunohistochemical localization of Na(+)/K(+)-ATPase alpha1-, alpha2- and beta3-subunits were investigated in the kidney of these rats. RESULTS: Na(+)/K(+)-ATPase alpha1-subunit was abundantly expressed in the medullary collecting ducts of control animals, but the expression was markedly decreased in the diabetic state with concomitant decrease in its mRNA expression. Similar decreases were observed in the insulin-treated diabetic rats, whereas in the C-peptide-treated diabetic rats, there was no reduction in the alpha1-expression. The beta3-subunit was expressed in podocytes and parietal cells in the glomeruli, vascular endothelial cells, and cortical collecting ducts, but lesser signals were observed in the proximal and distal tubules. However, the beta3-subunit did not appear to be affected by the diabetic state. CONCLUSIONS: Diabetes selectively reduced Na(+)/K(+)-ATPase alpha1-subunit expression and abundance. Chronic administration of C-peptide prevented this decrease. This implies a role for C-peptide in the long-term regulation of Na(+)/K(+)-ATPase function.
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| 24. |
- Nordquist, Lina, et al.
(författare)
-
Proinsulin C-peptide reduces diabetes-induced glomerular hyperfiltration via efferent arteriole dilation and inhibition of tubular sodium reabsorption
- 2009
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Ingår i: American Journal of Physiology - Renal Physiology. - : American Physiological Society. - 0363-6127 .- 1522-1466 .- 1931-857X. ; 297:5, s. F1265-F1272
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Tidskriftsartikel (refereegranskat)abstract
- C-peptide reduces diabetes-induced glomerular hyperfiltration in diabetic patients and experimental animal models. However, the mechanisms mediating the beneficial effect of C-peptide remain unclear. We investigated whether altered renal afferent-efferent arteriole tonus or alterations in tubular Na+ transport (T(Na)) in response to C-peptide administration mediate the reduction of diabetes-induced glomerular hyperfiltration. Glomerular filtration rate, filtration fraction, total and cortical renal blood flow, total kidney O2 consumption (QO2), T(Na), fractional Na+ and Li+ excretions, and tubular free-flow and stop-flow pressures were measured in anesthetized adult male normoglycemic and streptozotocin-diabetic Sprague-Dawley rats. The specific effect of C-peptide on transport-dependent QO2 was investigated in vitro in freshly isolated proximal tubular cells. C-peptide reduced glomerular filtration rate (-24%), stop-flow pressure (-8%), and filtration fraction (-17%) exclusively in diabetic rats without altering renal blood flow. Diabetic rats had higher baseline T(Na) (+40%), which was reduced by C-peptide. Similarly, C-peptide increased fractional Na+ (+80%) and Li+ (+47%) excretions only in the diabetic rats. None of these parameters was affected by vehicle treatments in either group. Baseline QO2 was 37% higher in proximal tubular cells from diabetic rats than controls and was normalized by C-peptide. C-peptide had no effect on ouabain-pretreated diabetic cells from diabetic rats. C-peptide reduced diabetes-induced hyperfiltration via a net dilation of the efferent arteriole and inhibition of tubular Na+ reabsorption, both potent regulators of the glomerular net filtration pressure. These findings provide new mechanistic insight into the beneficial effects of C-peptide on diabetic kidney function.
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| 25. |
- Nordquist, Lina, 1977-, et al.
(författare)
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Renal and vascular benefits of C-peptide : Molecular mechanisms of C-peptide action
- 2008
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Ingår i: Biologics. - 1177-5475 .- 1177-5491. ; 2:3, s. 441-452
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Tidskriftsartikel (refereegranskat)abstract
- C-peptide has long been thought to be an inert byproduct of insulin production, but it has become apparent, and accepted, that C-peptide has important biological properties. C-peptide displays beneficial effects in many tissues affected by diabetic complications, such as increased peripheral blood flow and protection from renal damage. However, the mechanisms mediating these effects remain unclear. C-peptide interacts with cellular membranes at unidentified sites distinctive of the insulin family of receptors, and signals to multiple targets known to play a role in diabetes and diabetic complications, such as Na(+)/K(+)-ATPase and NOS. In general, the physiological and molecular effects of C-peptide resemble insulin, but C-peptide also possesses traits separate from those of insulin. These basic studies have been confirmed in human studies, suggesting that C-peptide may lend itself to clinical applications. However, the molecular and physiological properties of C-peptide are not completely elucidated, and large clinical studies have not begun. In order to further these goals, we critically summarize the current state of knowledge regarding C-peptide's renal and vascular effects and the molecular signaling of C-peptide.
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| 26. |
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| 27. |
- Nordquist, Lina, et al.
(författare)
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Stay-at-home laboratory experiments - A case study of student motivation
- 2006
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Ingår i: WMSCI 2006: 10TH WORLD MULTI-CONFERENCE ON SYSTEMICS, CYBERNETICS AND INFORMATICS, VOL VII, PROCEEDINGS. - 9806560728 - 9789806560727 ; , s. 114-116
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Konferensbidrag (refereegranskat)abstract
- Background: Studies have reported that as many as 60 % of all students learn in a practical manner, rather than theoretically. However, Internet courses, tight budgets and increasing student numbers augments the demand for laboratory experiments carried out off the university premises. Methods: This pilot study was performed to investigate whether laboratory experiments in physiology performed at home are motivating for, stimulates depth understanding and increases student learning. Pharmacy students were recruited to the project from a five-week physiology course, and were given instruc tions on four stay-at-home experiments. These experiments were then discussed at a seminar. In conjunction to this seminar, a simple survey was filled in by the students. Comments: Our results indicated that this method of learning would be appreciated by the students. Stay-at-home laboratory experiments can never take the place of ordinary laboratory experiments, but could be beneficial as a supplement, not the least by introducing an everyday perspective to the students, allowing them to reflect on connections and relations in every day life.
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| 28. |
- Nordquist, Lina, 1977-, et al.
(författare)
-
The C-peptide fragment EVARQ reduces glomerular hyperfiltration in streptozotocin-induced diabetic rats
- 2007
-
Ingår i: Diabetes/Metabolism Research Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 23:5, s. 400-405
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Initially, diabetes is commonly associated with an increased glomerular filtration rate (GFR), a potential mechanism involved in the progression of diabetic nephropathy. Several studies have reported reno-protective effects of C-peptide. C-peptide reduces diabetes-induced hyperfiltration, as well as renal hypertrophy and albuminuria. In order to gain further understanding of these effects, it is very important to localize the active sites within the C-peptide molecule. This study was designed to elucidate the effects of the C-peptide fragment EVARQ on kidney function, blood pressure and blood glucose levels in diabetic rats in vivo. METHODS The study was performed on adult inactin-anaesthetized male Sprague-Dawley rats. Two weeks prior to the experiment, diabetes was induced by a single intravenous injection of streptozotocin (55 mg/kg BW). After recovery and recording of baseline values, vehicle, C-peptide (50 pmol . kg BW(-1).h(-1)) or EVARQ (500 pmol.kg BW(-1).h(-1)) was continuously administered for a total of 100 min. RESULTS Before substance administration, all diabetic groups displayed a pronounced hyperfiltration as compared to the control rats. Continuous administration of both C-peptide and EVARQ reduced the diabetes-induced hyperfiltration within an hour. Furthermore, blood pressure was only reduced in diabetic rats that were given C-peptide, whereas the blood glucose decreased in the diabetic groups that were given either C-peptide or EVARQ. CONCLUSIONS The present study shows that administration of the C-peptide fragment EVARQ has similar effects on GFR and blood glucose levels as the intact C-peptide molecule, suggesting at least one active site within this region.
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| 29. |
- Nordquist, Lina, 1977-, et al.
(författare)
-
The effect of amiloride during infusion of oxytocin in male sprague-dawley rats : a study of a possible intrarenal target site for oxytocin
- 2008
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Ingår i: Clinical and experimental hypertension (1993, Print). - : Informa UK Limited. - 1064-1963 .- 1525-6006. ; 30:2, s. 151-158
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Tidskriftsartikel (refereegranskat)abstract
- A possible natriuretic mechanism of action of oxytocin was investigated in male Sprague-Dawley rats. The effects of an intravenous bolus injection of amiloride on urine volume, potassium and sodium excretion, and osmolality were measured with and without an intravenous infusion of oxytocin in saline. Control values were obtained during the infusion of saline. Amiloride administered during an oxytocin infusion increased sodium excretion from 0.1 +/- 0.0 to 16.6 +/- 2.1 micromol/min. In animals treated with amiloride only, the sodium excretion was 4.5 +/- 0.8 micromol/min. The administration of oxytocin only resulted in a sodium excretion of 1.2 +/- 0.3 micromol/min. After the administration of oxytocin, amiloride increased urinary flow from 4.3 +/- 0.6 microl/min to 48.8 +/- 6.1 microl/min. In animals treated with amiloride only, the flow after the bolus dose was 17.7 +/- 1.8 microl/min. The administration of oxytocin only resulted in a flow of 8.5 +/- 1.6 microl/min. The amiloride-caused change in potassium excretion was not inhibited by oxytocin. In summary, the effects of amiloride were not inhibited by the actions of oxytocin. Amiloride administrated after reaching a near steady-state effect of oxytocin was found to give rise to an effect far greater than that after the administration of oxytocin or amiloride alone. It is concluded that the intrarenal natriuretic mechanisms of oxytocin do not emanate from the amiloride-sensitive sodium channels.
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| 30. |
- Palm, Fredrik, 1973-, et al.
(författare)
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Diabetesnefropati
- 2014. - 4
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Ingår i: Njurmedicin. - Stockholm : Liber. - 9789147114320 ; , s. 112-123
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 31. |
- Palm, Fredrik, 1973-, et al.
(författare)
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Diabetic nephropathy
- 2010. - 1
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Ingår i: Oxidative Stress in Basic Research and Clinical Practice. - New York, NY : Humana Press/Springer Science.
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Bokkapitel (refereegranskat)
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| 32. |
- Palm, Fredrik, et al.
(författare)
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Nitric oxide in the kidney : Direct measurements of bioavailable renal nitric oxide
- 2008
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Ingår i: Advances in Experimental Medicine and Biology. - Boston, MA : Springer US. - 0065-2598 .- 2214-8019. - 9780387717630 ; 599, s. 117-123
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Tidskriftsartikel (refereegranskat)abstract
- Increasing efforts have been directed towards investigating the involvement of nitric oxide (NO) for normal kidney function. Recently, a crucial role of NO in the development of progressive renal dysfunction has been reported during diabetes and hypertension. Indirect estimation of renal NO production include urinary nitrite/nitrate measurements, but there are several disadvantages of indirect methods since production and bioavailability of NO rarely coincide. Thus, direct measurement of in vivo NO bioavailability is preferred, although these methods are more time consuming and require highly specialized equipment and knowledge. This review focuses on two techniques for in vivo measurement of bioavailable NO in the kidney. We have applied Whalen-type recessed NO microsensors for measurement of NO in the kidney cortex, whereas the hemoglobin-trapping technique seems to be more suitable for NO measurement in the renal medulla. Both methods are robust and reliable, and we discuss advantages and shortcomings of each method.
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| 33. |
- Palm, Fredrik, et al.
(författare)
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Renal oxidative stress, oxygenation and hypertension
- 2011
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Ingår i: American Journal of Physiology. Regulatory Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 301:5, s. R1229-R1241
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Tidskriftsartikel (refereegranskat)abstract
- Hypertension is closely associated with progressive kidney dysfunction, manifested as glomerulosclerosis, interstitial fibrosis, proteinuria and eventually declining glomerular filtration. The postulated mechanism for development of glomerulosclerosis is barotrauma caused by increased capillary pressure, but the reason for development of interstitial fibrosis and the subsequently reduced kidney function is less clear. However, it has been hypothesized that tissue hypoxia induces fibrogenesis and progressive renal failure. This is very interesting, since recent reports highlight several different mechanisms resulting in altered oxygen handling and availability in the hypertensive kidney. Such mechanisms include decreased renal blood flow due to increased vascular tone induced by angiotensin II that limits oxygen delivery, increased oxidative stress resulting in increased mitochondrial oxygen usage, increased oxygen usage for tubular electrolyte transport and shunting of oxygen from arterial to venous blood in preglomerular vessels. It has been shown in several studies that interventions to prevent oxidative stress and to restore kidney tissue oxygenation prevent progression of kidney dysfunction. Furthermore, inhibition of angiotensin II activity, by either blocking AT(1)-receptors or angiotensin converting enzyme, or by preventing oxidative stress by administration of antioxidants also results in improved blood pressure control. It therefore seems likely that tissue hypoxia in the hypertensive kidney contributes to progression of kidney damage and perhaps also maintaining the high blood pressure.
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| 34. |
- Palm, Fredrik, et al.
(författare)
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Renal tubulointerstitial hypoxia : Cause and consequence of kidney dysfunction
- 2011
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Ingår i: Clinical and experimental pharmacology & physiology. - : Wiley. - 0305-1870 .- 1440-1681. ; 38:7, s. 424-430
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Tidskriftsartikel (refereegranskat)abstract
- 1. Intrarenal oxygen availability is the balance between supply, mainly dependent on renal blood flow, and demand, determined by the basal metabolic demand and the energy-requiring tubular electrolyte transport. Renal blood flow is maintained within close limits in order to sustain stable glomerular filtration, so increased intrarenal oxygen consumption is likely to cause tissue hypoxia.2. The increased oxygen consumption is closely linked to increased oxidative stress, which increases mitochondrial oxygen usage and reduces tubular electrolyte transport efficiency, with both contributing to increased total oxygen consumption.3. Tubulointerstitial hypoxia stimulates the production of collagen I and alpha-smooth muscle actin, indicators of increased fibrogenesis. Furthermore, the hypoxic environment induces epithelial-mesenchymal transdifferentiation and aggravates fibrosis, which results in reduced peritubular blood perfusion and oxygen delivery due to capillary rarefaction.4. Increased oxygen consumption, capillary rarefaction and increased diffusion distance due to the increased fibrosis per se further aggravate the interstitial hypoxia.5. Recently, it has been demonstrated that hypoxia simulates the infiltration and maturation of immune cells, which provides an explanation for the general inflammation commonly associated with the progression of chronic kidney disease. 6. Therapies targeting interstitial hypoxia could potentially reduce the progression of chronic renal failure in millions of patients who are otherwise likely to eventually present with fully developed end-stage renal disease.
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| 35. |
- Palm, Fredrik, et al.
(författare)
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Uremia induces abnormal oxygen consumption in tubules and aggravates chronic hypoxia of the kidney via oxidative stress
- 2010
-
Ingår i: American Journal of Physiology - Renal Physiology. - : American Physiological Society. - 0363-6127 .- 1522-1466 .- 1931-857X. ; 299:2, s. F380-F386
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Tidskriftsartikel (refereegranskat)abstract
- In addition to causing uremic symptoms, uremic toxins accelerate the progression of renal failure. To elucidate the pathophysiology of uremic states, we investigated the effect of indoxyl sulfate (IS), a representative uremic toxin, on oxygen metabolism in tubular cells. We demonstrated an increase in oxygen consumption by IS in freshly isolated rat and human proximal tubules. Studies utilizing ouabain, the Na-K-ATPase inhibitor, and apocynin, the NADPH oxidase inhibitor, as well as the in vivo gene-silencing approach to knock down p22(phox) showed that the increase in tubular oxygen consumption by IS is dependent on Na-K-ATPase and oxidative stress. We investigated whether the enhanced oxygen consumption led to subsequent hypoxia of the kidney. An increase in serum IS concentrations in rats administered indole was associated with a decrease in renal oxygenation (8 h). The remnant kidney in rats developed hypoxia at 16 wk. Treatment of the rats with AST-120, an oral adsorbent that removes uremic toxins, reduced serum IS levels and improved oxygenation of the kidney. Amelioration of hypoxia in the remnant kidney was associated with better renal functions and less histological injury. Reduction of serum IS levels also led to a decrease in oxidative stress in the kidney. Our ex vivo and in vivo studies implicated that uremic states may deteriorate renal dysfunction via dysregulating oxygen metabolism in tubular cells. The abnormal oxygen metabolism in tubular cells by uremic toxins was, at least in part, mediated by oxidative stress.
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| 36. |
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| 37. |
- Roxhed, Niclas, et al.
(författare)
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Painless drug delivery through microneedle-based transdermal patches featuring active infusion
- 2008
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Ingår i: IEEE Transactions on Biomedical Engineering. - 0018-9294 .- 1558-2531. ; 55:3, s. 1063-1071
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Tidskriftsartikel (refereegranskat)abstract
- This paper presents the first microneedle-based transdermal patch with integrated active dispensing functionality. The electrically controlled system consists of a low-cost dosing and actuation unit capable of controlled release of liquid in the microliter range at low flow-rates and minimally invasive, side-opened, microneedles. The system was successfully tested in vivo by insulin administration to diabetic rats. Active infusion of insulin at 2 mul/h was compared to passive, diffusion-driven, delivery. Continuous active infusion caused significantly higher insulin concentrations in blood plasma. After a 3-h delivery period, the insulin concentration was five times larger compared to passive delivery. Consistent with insulin concentrations, actively administered insulin resulted in a significant decrease of blood glucose levels. Additionally, insertion and liquid injection was verified on human skin. This study shows the feasibility of a patch-like system with on-board liquid storage and dispensing capability. The proposed device represents a first step towards painless and convenient administration of macromolecular drugs such as insulin or vaccines.
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| 38. |
- Singh, P., et al.
(författare)
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Renal oxygenation and haemodynamics in acute kidney injury and chronic kidney disease
- 2013
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Ingår i: Clinical and Experimental Pharmacology and Physiology. - : Wiley. - 0305-1870 .- 1440-1681. ; 40:2, s. 138-147
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Tidskriftsartikel (refereegranskat)abstract
- Acute kidney injury (AKI) is a major burden on health systems and may arise from multiple initiating insults, including ischaemia-reperfusion injury, cardiovascular surgery, radiocontrast administration and sepsis. Similarly, the incidence and prevalence of chronic kidney disease (CKD) continues to increase, with significant morbidity and mortality. Moreover, an increasing number of AKI patients survive to develop CKD and end-stage renal disease. Although the mechanisms for the development of AKI and progression to CKD remain poorly understood, initial impairment of oxygen balance likely constitutes a common pathway, causing renal tissue hypoxia and ATP starvation that, in turn, induce extracellular matrix production, collagen deposition and fibrosis. Thus, possible future strategies for one or both conditions may involve dopamine, loop diuretics, atrial natriuretic peptide and inhibitors of inducible nitric oxide synthase, substances that target kidney oxygen consumption and regulators of renal oxygenation, such as nitric oxide and heme oxygenase-1.
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| 39. |
- Sivertsson, Ebba, et al.
(författare)
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Lowering plasma levels of protein-bound uremic toxins improves cardiac output and renal oxygenation in a rat model of chronic kidney disease
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Chronic kidney disease (CKD) is an increasing health problem which is closely associated with cardiac dysfunction. In CKD uremic toxins accumulate as kidney function declines. Indoxyl sulfate is a uremic toxin that induces kidney tissue hypoxia, proteinuria and kidney damage. Furthermore, high salt intake is a growing health issue worldwide. In this study, we investigated the effect of reducing plasma indoxyl sulfate in a rat model of CKD challenged with high salt intake and compared the effects to that of conventional treatment using an angiotensin converting enzyme inhibitor (ACEI). In rats, the right kidney and 2/3 of the left kidney were surgically removed (5/6 nephrectomy). Animals were fed a normal salt containing diet for four weeks and randomized to either vehicle or chronic treatment with either the oral absorbent AST-120 or the ACEI enalapril. Thereafter, kidney function was measured before and after a week of high salt intake. Cardiac output was measured at the end of the study period. A reduction of plasma levels of indoxyl sulfate by AST-120 improved cardiac output as well as urinary oxidative stress and proteinuria. ACEI reduced oxidative stress in kidney tissue and significantly improved proteinuria and the glomerular filtration rate in response to the high salt intake. Both interventions improved intrarenal oxygen availability.In conclusion, decreasing circulating levels of protein bound uremic toxins, e.g. indoxyl sulfate, improves cardiac output, reduces urinary oxidative stress and proteinuria in experimental CKD. Reduced angiotensin II signaling has direct reno-protective effects by decreasing intrarenal oxidative stress, protecting renal reserve and increasing urinary Na+ excretion during high salt intake. Both treatments had striking effects on cortical oxygen availability. A dual strategy, to reduce indoxyl sulfate and angiotensin II signaling simultaneously, could be an efficient strategy to target both cardiac and renal dysfunction in CKD, to further slow progression of disease.
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| 40. |
- Stridh, Sara, et al.
(författare)
-
C-peptide normalizes glomerular filtration rate in hyperfiltrating conscious diabetic rats
- 2009
-
Ingår i: Oxygen transport to tissue xxx. - New York : Springer. - 9780387859972 - 0387859977 - 9780387859989 ; , s. 219-225
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Bokkapitel (refereegranskat)abstract
- Tubular electrolyte transport accounts for a major part of the oxygen consumed by the normal kidney. We have previously reported a close association between diabetes and increased oxygen usage, partly due to increased tubular electrolyte transport secondary to glomerular hyperfiltration during the early onset of diabetes. Several studies have shown that acute administration of C-peptide to diabetic rats with glomerular hyperfiltration results in normalized glomerular filtration rate (GFR). In this study, we validated a novel method for precise and repetitive GFR measurements in conscious rats and used C-peptide injection in diabetic rats for evaluation. First, GFR was determined in normoglycemic control rats before and after C-peptide administration. Thereafter, all rats were made diabetic by an i.v. streptozotocin injection. Fourteen days later, GFR was again determined before and after C-peptide administration. GFR was estimated from plasma clearance curves using a single bolus injection of FITC-inulin, followed by serial blood sampling over 155 min. FITC-inulin clearance was calculated using non-compartmental pharmacokinetic data analysis. Baseline GFR in normoglycemic controls was 2.10 +/- 0.18 ml/min, and was unaffected by C-peptide (2.23 +/- 0.14 ml/min). Diabetic rats had elevated GFR (3.06 +/- .034 ml/min), which was normalized by C-peptide (2.35 +/- 0.30 ml/min). In conclusion, the used method for estimation of GFR in conscious animals result in values that are in good agreement with those obtained from traditional GFR measurements on anaesthetized rats. However, multiple measurements from the same conscious subject can be obtained using this method. Furthermore, as previously shown on anaesthetized rats, C-peptide also normalizes GFR in hyperfiltrating conscious diabetic rats.
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| 41. |
- Tiwari, Swasti, et al.
(författare)
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Trafficking of ENaC subunits in response to acute insulin in mouse kidney
- 2007
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Ingår i: American Journal of Physiology - Renal Physiology. - : American Physiological Society. - 0363-6127 .- 1522-1466 .- 1931-857X. ; 293:1, s. F178-F185
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Tidskriftsartikel (refereegranskat)abstract
- Studies done in cell culture have demonstrated that insulin activates the epithelial sodium channel (ENaC) via a variety of mechanisms. However, to date, upregulation of ENaC in native renal tissue by in vivo administration of insulin has not been demonstrated. To address this, we injected 6-mo-old male C57BL/CBA mice (n = 14/group) intraperitoneally with vehicle or 0.5 U/kg body wt insulin and examined short-term (1-2 h) sodium excretion and kidney ENaC subunits (alpha, beta, and gamma) and serum and glucocorticoid-induced kinase (SGK-1) regulation. Insulin resulted in a significant reduction in urine sodium (by approximately 80%) that was restored by intraperitoneal administration of the ENaC antagonist, benzamil (1.4 mg/kg body wt). Differential centrifugation followed by Western blotting of whole kidney revealed significantly increased band densities (by 26-103%) for insulin- relative to vehicle-treated mice for alpha- and gamma-ENaC in the homogenate (H), and plasma membrane-enriched fraction (MF), with no difference in the vesicle-enriched fraction (VF). Similarly, beta-ENaC was significantly increased in MF (by 45%) but no change in the H. It was, however, significantly decreased in the VF (by 28%) with insulin. In agreement, immunoperoxidase labeling demonstrated relatively stronger apical, relative to cytosolic, localization of alpha-, beta-, and gamma-ENaC with insulin, whereas, with vehicle, labeling was fairly evenly dispersed throughout collecting duct principal cells. Furthermore, Western blotting showed insulin increased SGK-1 (by 75%) and phosphorylated-SGK band densities (by 30%) but only in the MF. These studies demonstrate novel in vivo regulation of renal ENaC activity and subunit proteins and SGK-1 by insulin in the acute time frame in the mouse.
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