| 1. |
- Amin, Risul, et al.
(författare)
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The kidney injury caused by the onset of acute graft-versus-host disease is associated with down-regulation of alpha Klotho
- 2020
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Ingår i: International Immunopharmacology. - : Elsevier BV. - 1567-5769 .- 1878-1705. ; 78
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Tidskriftsartikel (refereegranskat)abstract
- Acute graft-versus-host disease (aGVHD) and kidney injury are the major complications after allogeneic hematopoietic stem cell transplantation (HSCT). Although the underlying mechanisms for the development of these complications are not yet fully understood, it has been proposed that emergence of aGVHD contributes to the development of kidney injury after HSCT. We have shown previously that aGVHD targets the kidney in a biphasic manner: at the onset, inflammatory genes are up-regulated, while when aGVHD becomes established, donor lymphocytes infiltrate the kidney. Here, we characterize renal manifestations at the onset of aGVHD. Mice receiving allogeneic bone marrow and spleen cells displayed symptoms of aGVHD and elevated serum levels of tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) within 4 days. There was concurrent kidney injury with the following characteristics: (1) elevated expression of the kidney injury biomarker, neutrophil gelatinase-associated lipocalin (NGAL), (2) accumulation of hetero-lysosomes in proximal tubule epithelial cells, and (3) reductions in alpha Klotho mRNA and protein and increased serum levels of fibroblast growth factor 23 (Fgf23), phosphate and urea. This situation resembled acute renal injury caused by bacterial lipopolysaccharide. We conclude that the onset of aGVHD is associated with kidney injury involving down-regulation of alpha Klotho, a sight that may inspire novel therapeutic approaches.
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| 2. |
- Charrin, Emmanuelle, et al.
(författare)
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Soluble Klotho protects against glomerular injury through regulation of ER stress response
- 2023
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Ingår i: Communications Biology. - : Springer Nature. - 2399-3642. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- alpha Klotho (Klotho) has well established renoprotective effects; however, the molecular pathways mediating its glomerular protection remain incompletely understood. Recent studies have reported that Klotho is expressed in podocytes and protects glomeruli through auto- and paracrine effects. Here, we examined renal expression of Klotho in detail and explored its protective effects in podocyte-specific Klotho knockout mice, and by overexpressing human Klotho in podocytes and hepatocytes. We demonstrate that Klotho is not significantly expressed in podocytes, and transgenic mice with either a targeted deletion or overexpression of Klotho in podocytes lack a glomerular phenotype and have no altered susceptibility to glomerular injury. In contrast, mice with hepatocyte-specific overexpression of Klotho have high circulating levels of soluble Klotho, and when challenged with nephrotoxic serum have less albuminuria and less severe kidney injury compared to wildtype mice. RNA-seq analysis suggests an adaptive response to increased endoplasmic reticulum stress as a putative mechanism of action. To evaluate the clinical relevance of our findings, the results were validated in patients with diabetic nephropathy, and in precision cut kidney slices from human nephrectomies. Together, our data reveal that the glomeruloprotective effects of Klotho is mediated via endocrine actions, which increases its therapeutic potential for patients with glomerular diseases. Transgenic overexpression of alpha Klotho in hepatocytes results in protection against renal insults, possibly through modulation of the ER stress response by circulating alpha Klotho. In contrast, alpha Klotho overexpressed in podocytes is not renoprotective.
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| 3. |
- Falkevall, Annelie, et al.
(författare)
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Reducing VEGF-B Signaling Ameliorates Renal Lipotoxicity and Protects against Diabetic Kidney Disease
- 2017
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 25:3, s. 713-726
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Tidskriftsartikel (refereegranskat)abstract
- Diabetic kidney disease (DKD) is the most common cause of severe renal disease, and few treatment options are available today that prevent the progressive loss of renal function. DKD is characterized by altered glomerular filtration and proteinuria. A common observation in DKD is the presence of renal steatosis, but the mechanism(s) underlying this observation and to what extent they contribute to disease progression are unknown. Vascular endothelial growth factor B (VEGF-B) controls muscle lipid accumulation through regulation of endothelial fatty acid transport. Here, we demonstrate in experimental mouse models of DKD that renal VEGF-B expression correlates with the severity of disease. Inhibiting VEGF-B signaling in DKD mouse models reduces renal lipotoxicity, re-sensitizes podocytes to insulin signaling, inhibits the development of DKD-associated pathologies, and prevents renal dysfunction. Further, we show that elevated VEGF-B levels are found in patients with DKD, suggesting that VEGF-B antagonism represents a novel approach to treat DKD.
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| 4. |
- Grigore, Teodora V. V., et al.
(författare)
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Fibroblast growth factor 23 is independently associated with renal magnesium handling in patients with chronic kidney disease
- 2023
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Ingår i: Frontiers in Endocrinology. - : FRONTIERS MEDIA SA. - 1664-2392. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundDisturbances in magnesium homeostasis are common in patients with chronic kidney disease (CKD) and are associated with increased mortality. The kidney is a key organ in maintaining normal serum magnesium concentrations. To this end, fractional excretion of magnesium (FEMg) increases as renal function declines. Despite recent progress, the hormonal regulation of renal magnesium handling is incompletely understood. Fibroblast Growth Factor 23 (FGF23) is a phosphaturic hormone that has been linked to renal magnesium handling. However, it has not yet been reported whether FGF23 is associated with renal magnesium handling in CKD patients. MethodsThe associations between plasma FGF23 levels, plasma and urine magnesium concentrations and FEMg was investigated in a cross-sectional cohort of 198 non-dialysis CKD patients undergoing renal biopsy. ResultsFGF23 was significantly correlated with FEMg (Pearsons correlation coefficient = 0.37, p<0.001) and urinary magnesium (-0.14, p=0.04), but not with plasma magnesium. The association between FGF23 and FEMg remained significant after adjusting for potential confounders, including estimated glomerular filtration rate (eGFR), parathyroid hormone and 25-hydroxyvitamin D. ConclusionsWe report that plasma FGF23 is independently associated with measures of renal magnesium handling in a cohort of non-dialysis CKD patients. A potential causal relationship should be investigated in future studies.
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| 5. |
- Krajisnik, Tijana, et al.
(författare)
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Parathyroid Klotho and FGF-receptor 1 expression decline with renal function in hyperparathyroid patients with chronic kidney disease and kidney transplant recipients
- 2010
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Ingår i: Kidney International. - : Elsevier BV. - 0085-2538 .- 1523-1755. ; 78:10, s. 1024-1032
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Tidskriftsartikel (refereegranskat)abstract
- Current studies suggest that short-term exposure of parathyroid glands to fibroblast growth factor 23 (FGF23) reduces parathyroid hormone secretion. However, patients with chronic kidney disease (CKD) develop secondary hyperparathyroidism despite high levels of serum FGF23, indicating a parathyroid FGF23 'resistance'. Here we analyzed the expression of the FGF23 receptors Klotho and FGF receptor 1 (FGFR1) in 88 hyperplastic parathyroid glands from 31 patients with CKD (including 21 renal allograft recipients), and their regulation in isolated bovine and human hyperplastic parathyroid cells. Glandular expression was variable, yet the Klotho and FGFR1 mRNA levels declined in parallel with the decreasing glomerular filtration rate, significantly decreasing over CKD stages. We found no association between the expression of Klotho, FGFR1, and the proliferation marker Ki67. In vitro treatment of bovine cells with FGF23 or calcium reduced the Klotho level, whereas active vitamin D-3 compounds increased its expression. Phosphate and parathyroid hormone had no effect. Treatment had less impact on Klotho in cultured human cells than in the bovine healthy cell model, whereas FGFR1 expression was induced in the hyperplastic cells. Thus parathyroid Klotho and FGFR1 decrease with declining renal function, possibly because of alterations in mineral metabolism related to the failing kidney. This could explain the observed parathyroid resistance to FGF23 in late CKD.
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| 6. |
- Krajisnik, Tijana, 1981-, et al.
(författare)
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Parathyroid Klotho Expression Declines with Renal Function in Hyperparathyroid CKD Patients
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Current data suggest that type I membrane-bound α-Klotho plays a dual role in the regulation of PTH secretion. While stimulating PTH release during hypocalcemia, Klotho inhibits PTH production by mediating the suppressive effect of fibroblast growth factor-23 (FGF23). In chronic kidney disease (CKD), secondary hyperparathyroidism (sHPT) often develops in the presence of high serum FGF23, indicating parathyroid resistance to FGF23 action. This could in part be due to reduced Klotho expression, as reported in kidneys of CKD patients. Herein, we analyzed parathyroid Klotho expression level in 31 patients with sHPT as well as regulation of Klotho in isolated bovine parathyroid cells using real-time PCR analysis and IHC staining. Klotho expression was variable in secondary hyperplastic glands, yet the mRNA levels correlated positively with glomerular filtration rate and significantly decreased over CKD stages. In vitro treatment with either FGF23 or calcium dose-dependently reduced the Klotho level, whereas vitamin D treatment increased its expression. This stimulatory effect was blunted in the presence of either high FGF23 or calcium. No effect on Klotho level was observed after treatment with phosphate or PTH. In summary, parathyroid Klotho expression was variable in sHPT but decreased with declining renal function. This may be due to a complex co-regulation by calcium, FGF23 and vitamin D, and explain the lack of suppressive effects of FGF23 on PTH secretion in late CKD.
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| 7. |
- Larsson, Tobias E, et al.
(författare)
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Conjoint effects of serum calcium and phosphate on risk of total, cardiovascular, and noncardiovascular mortality in the community
- 2010
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1079-5642 .- 1524-4636. ; 30:2, s. 333-339
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Hyperphosphatemia is a cardiovascular risk factor in patients with chronic kidney disease. Relations of circulating calcium (Ca) and phosphorus (Pi) to long-term mortality risk in the community require further investigation. METHODS AND RESULTS: Associations of serum Ca and Pi to mortality were evaluated in a community-based cohort of 2176 men (mean age, 50.1 years). During follow-up (median, 29.8 years), 1009 men died, and 466 of these deaths resulted from cardiovascular causes. In Cox proportional hazards models, serum Pi and [CaxPi] were independent predictors of total mortality (hazard ratio per SD, 1.06; 95% CI, 1.01-1.12; P=0.03; 1.07; 95% CI, 1.01-1.12; P=0.01) and cardiovascular mortality (1.10; 95% CI, 1.02-1.18; P=0.01; 1.10; 95% CI, 1.03-1.19; P=0.008). Serum Ca was associated with risk of total mortality (1.08; 95% CI, 1.01-1.16; P=0.02) and noncardiovascular mortality (1.10; 95% CI, 1.01-1.21; P=0.04). Results were consistent after multivariate adjustments in subsamples of individuals with estimated glomerular filtration rate >90 mL/min and low-to-normal serum Ca and Pi. CONCLUSIONS: Circulating Ca and Pi levels are associated with risks of total, cardiovascular, and noncardiovascular mortality in the community, and their conjoint effects are additive. Additional studies are warranted to evaluate whether Ca and Pi are modifiable risk factors in the general population.
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| 8. |
- Olauson, Hannes, et al.
(författare)
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A novel missense mutation in GALNT3 causing hyperostosis-hyperphosphataemia syndrome
- 2008
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Ingår i: European Journal of Endocrinology. - Bristol : BioScientifica Ltd. - 0804-4643 .- 1479-683X. ; 158:6, s. 929-934
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Hyperostosis–hyperphosphataemia syndrome (HHS) is a rare hereditary disorder characterized by hyperphosphataemia, inappropriately normal or elevated 1,25-dihydroxyvitamin D3 and localized painful cortical hyperostosis. HHS was shown to be caused by inactivating mutations in GALNT3, encoding UDP-N-acetyl-a-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase 3 (GalNAc-transferase; GALNT3). Herein,we sought to identify the genetic cause of hyperphosphataemia and tibial hyperostosis in a 19-year-old girl of Colombian origin. Methods: Genomic DNA was extracted and sequencing analysis of the GALNT3 and fibroblast growth factor 23 (FGF23) genes performed. Serum levels of intact and C-terminal FGF23 were measured using two different ELISA methods. Results: Mutational analysis identified a novel homozygous missense mutation in exon 6 of GALNT3 (1584 GOA), leading to an amino acid shift from Arg to His at residue 438 (R438H). The mutation was not found in over 200 control alleles or in any single nucleotide polymorphism databases. The R438 residue is highly conserved throughout species and in all known GalNAc-transferase family members. Modelling predicted the substitution deleterious for protein structure. Importantly, the phosphaturic factor FGF23 was differentially processed, as reflected by low intact (15 pg/ml) but high C-terminal (839 RU/ml) serum FGF23 levels. Conclusions: We report on the first missense mutation in GALNT3 giving rise to HHS, since previous GALNT3 mutations in HHS caused aberrant splicing or premature truncation of the protein. The R438H substitution likely abrogates GALNT3 activity, in turn causing enhanced FGF23 degradation and subsequent hyperostosis/hyperphosphataemia.
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| 9. |
- Olauson, Hannes
(författare)
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The role of FGF23/Klotho in mineral metabolism and chronic kidney disease
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chronic kidney disease (CKD) is a global health burden of growing incidence and prevalence. As renal function declines disturbances in mineral metabolism, such as hyperphosphatemia and secondary hyperparathyroidism, inevitably develop. These metabolic changes are closely associated with poor prognosis and survival. The bone-derived hormone fibroblast growth factor-23 (FGF23) and its co-receptor Klotho represent a novel endocrine axis regulating mineral metabolism in health and disease. FGF23-Klotho signalling inhibits renal phosphate reabsorption and activation of vitamin D, and reduces secretion of parathyroid hormone (PTH). Serum levels of FGF23 rise at early stages of CKD, presumably due to increased phosphate load, and numerous studies identify elevated FGF23 as a predictor of adverse clinical outcome. In contrast, tissue expression of Klotho decreases in parallel with CKD progression and reaches low or undetectable levels in end-stage renal disease. Importantly, mice lacking Klotho develop numerous complications associated with accelerated ageing, and many patients with advanced CKD, a state of Klotho deficiency, display a similar senescence-like phenotype. Altogether, FGF23 excess and lack of Klotho may be key pathogenic factors in CKD. In the present thesis we sought to elucidate the role of renal and parathyroid FGF23-Klotho signalling in physiology and in CKD. In Study I we investigate Klotho levels in surgically resected parathyroid tissue specimen from CKD patients with secondary hyperparathyroidism, and find diminished Klotho expression paralleling the decline in renal function. Further, we demonstrate that FGF23 dose-dependently suppresses Klotho in bovine parathyroid cell culture, indicating a ligand-receptor regulatory process. In Study II we generate parathyroid-specific Klotho knockout mice (PTH-KL-/-) using Cre-Lox recombination. PTH-KL-/- mice display a normal gross phenotype with a preserved calcium-PTH axis. Their PTH response is similar to wild-type mice when treated with FGF23 or challenged with renal failure. Yet, FGF23 treatment activates the MAPK pathway in wild-type mice but not in PTH-KL-/- mice. Importantly, blocking of calcineurin with cyclosporine A abolishes the FGF23-mediated PTH suppression in PTH-KL-/- mice, whereas wild-type mice remain responsive. Thus, we identify a novel calcineurin-dependent pathway in the parathyroid glands that, in the absence of Klotho, mediates acute suppression of PTH secretion by FGF23. In Study III we develop a novel, non-surgical, mouse model of tubulointerstitial nephropathy. By adding various concentrations of adenine to the diet we define an adjustable protocol for inducing and maintaining uremia in mice. In Study IV we generate distal tubule-specific Klotho knockout mice (Ksp-KL-/-). In contrast to systemic Klotho knockout mice, Ksp-KL-/- mice are fertile with a normal gross phenotype. Adult Ksp-KL-/- mice are hyperphosphatemic, indicating attenuated effects of FGF23 on proximal tubular phosphate handling. Further, FGF23 is higher in Ksp-KL-/- mice than in wild-type mice with matched serum phosphate, suggesting phosphate-independent regulation of FGF23 in Ksp-KL-/- mice. Collectively, the studies presented in this thesis identify several novel and critical aspects of FGF23-Klotho signalling and function in health and disease, and provide important tools allowing for continuous investigation.
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| 10. |
- Westerberg, Per-Anton, et al.
(författare)
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Preoperative tumor localization by means of venous sampling for fibroblast growth factor-23 in a patient with tumor-induced osteomalacia
- 2008
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Ingår i: Endocrine Practice. - 1530-891X .- 1934-2403. ; 14:3, s. 362-7
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To report on a novel strategy for tumor localization in a 62-year-old man with hypophosphatemic tumor-induced osteomalacia (TIO). METHODS: Repeated computed tomographic and magnetic resonance imaging scans failed to localize any tumor in a patient with adult-onset hypophosphatemic osteomalacia. Therefore, venous sampling for fibroblast growth factor-23 (FGF23)--a circulating hormone that has been identified as a causative factor for TIO--in major veins was conducted. Serum FGF23 was measured from collected samples by an intact FGF23 enzyme-linked immunosorbent assay. RESULTS: Venous sampling suggested a local increase in serum FGF23 in the left femoral vein; this finding prompted performance of octreotide scintigraphy restricted to the left leg. A tumor was located at the lateral condyle of the left femur, which was also confirmed by magnetic resonance imaging. Surgical resection of the tumor normalized the serum phosphorus and 1,25-dihydroxyvitamin D3 levels within 5 to 10 days, and FGF23 declined to normal levels within 24 hours. Histologic analysis supported the diagnosis of a soft-tissue giant cell tumor. CONCLUSION: Our study case demonstrates the diagnostic complexity and difficulties in localizing a small tumor in a patient with TIO. Venous sampling for FGF23 may be helpful in tumor localization in sporadic cases of hypophosphatemic osteomalacia, especially when noninvasive diagnostic techniques prove insufficient.
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