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- Levin, A., et al.
(author)
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Novel insights into the disease transcriptome of human diabetic glomeruli and tubulointerstitium
- 2020
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In: Nephrology Dialysis Transplantation. - : Oxford University Press (OUP). - 0931-0509 .- 1460-2385. ; 35:12, s. 2059-2072
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Journal article (peer-reviewed)abstract
- Background. Diabetic nephropathy (DN) is the most common cause of end-stage renal disease, affecting similar to 30% of the rapidly growing diabetic population, and strongly associated with cardiovascular risk. Despite this, the molecular mechanisms of disease remain unknown. Methods. RNA sequencing (RNAseq) was performed on paired, micro-dissected glomerular and tubulointerstitial tissue from patients diagnosed with DN [n = 19, 15 males, median (range) age: 61 (30-85) years, chronic kidney disease stages 1-4] and living kidney donors [n = 20, 12 males, median (range) age: 56 (30-70) years]. Results. Principal component analysis showed a clear separation between glomeruli and tubulointerstitium transcriptomes. Differential expression analysis identified 1550 and 4530 differentially expressed genes, respectively (adjusted P < 0.01). Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses highlighted activation of inflammation and extracellular matrix (ECM) organization pathways in glomeruli, and immune and apoptosis pathways in tubulointerstitium of DN patients. Specific gene modules were associated with renal function in weighted gene co-expression network analysis. Increased messengerRNA (mRNA) expression of renal damage markers lipocalin 2 (LCN) and hepatitis A virus cellular receptor1 (HAVCR1) in the tubulointerstitial fraction was observed alongside higher urinary concentrations of the corresponding proteins neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) in DN patients. Conclusions. Here we present the first RNAseq experiment performed on paired glomerular and tubulointerstitial samples from DN patients. We show that prominent disease-specific changes occur in both compartments, including relevant cellular processes such as reorganization of ECM and inflammation (glomeruli) as well as apoptosis (tubulointerstitium). The results emphasize the potential of utilizing high-throughput transcriptomics to decipher disease pathways and treatment targets in this high-risk patient population.
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- Axelsson, J, et al.
(author)
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Serum retinol-binding protein concentration and its association with components of the uremic metabolic syndrome in nondiabetic patients with chronic kidney disease stage 5
- 2009
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In: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 29:5, s. 447-53
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Journal article (peer-reviewed)abstract
- <i>Introduction:</i> Chronic kidney disease (CKD) is associated with insulin resistance also in the absence of overt diabetes mellitus. The liver-derived transport protein retinol-binding protein (RBP) has recently been proposed as a novel adipokine involved in the metabolism of glucose. Although RBP is elevated in type 2 diabetics with mild CKD, its role in advanced CKD is not well studied. We hypothesized that altered RBP levels in CKD could be one factor contributing to the uremic insulin resistance. <i>Patients and Methods:</i> In a cross-sectional study, we evaluated 141 nondiabetic stage 5 CKD patients (GFR 6.8 ± 2.0 ml/min; 62% males, mean age 52 ± 11 years) close to the start of renal replacement therapy. We studied circulating RBP (RIA), retinol and metabolic markers. Body composition was also assessed using DEXA and patients were divided according to truncal fat mass above (obese) or below (lean) the sex-specific median. A fasting plasma glucose ≥6.1 m<i>M</i> was defined as impaired glucose tolerance (IGT). <i>Results:</i> Serum RBP levels were significantly elevated in CKD as compared to previous reports in non-renal patients. Whereas levels of RBP did not differ between lean and obese patients without IGT, they were lower in lean CKD patients with IGT (5.9 ± 2.9 μ<i>M</i>) than in obese CKD patients with IGT (7.0 ± 2.9 μ<i>M</i>; p < 0.05). While RBP did not correlate with truncal or total fat mass or biomarkers of inflammation, in univariate analysis, we found weak correlations with HbA1c% (rho = 0.17; p < 0.05), fasting serum triglycerides (rho = 0.20; p < 0.001) and fasting apolipoprotein (Apo) A1 (rho = 0.29; p < 0.001). RBP also correlated negatively with ApoB (rho = –0.29; p < 0.001). In multivariate analysis, RBP was a significant and independent predictor of both HbA1c% and ApoA1 levels. Finally, RBP was strongly correlated with serum retinol, and calculating a retinol/RBP index further strengthened the observed correlations with HOMA-IR and HbA1c%. <i>Conclusions:</i> RBP is elevated in nondiabetic stage 5 CKD and correlates weakly with HbA1c and ApoA1. As RBP is thought to induce insulin resistance and directly affect lipoprotein metabolism in other disease states, these findings may support a role for RBP in contributing to the uremic metabolic syndrome, putatively by altering ApoA1 metabolism, but further studies are needed to test this hypothesis.
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- Levin, A, et al.
(author)
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Serum Glutaredoxin Activity as a Marker of Oxidative Stress in Chronic Kidney Disease: A Pilot Study
- 2018
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In: Nephron. - : S. Karger AG. - 2235-3186 .- 1660-8151. ; 140:4, s. 249-256
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Journal article (peer-reviewed)abstract
- <b><i>Background:</i></b> Inflammation and oxidative stress play important roles in the pathogenesis and progression of chronic kidney disease (CKD) and in its complications, in particular cardiovascular disease, a major cause of death among patients undergoing dialysis treatment. We recently described that Glutaredoxin1 (Grx), an intracellular antioxidant, catalyzes oxidoreductase reactions also extracellularly, and that serum Grx levels correlate to disease severity in type 2 diabetes. <b><i>Aim:</i></b> In the current study we assess Grx as a potential clinical marker of oxidative stress in CKD. <b><i>Methods:</i></b> We examined Grx activity in 25 patients with different stages of chronic kidney failure, 19 control subjects, and 36 patients at initiation of dialysis and after 2 years of dialysis. <b><i>Results:</i></b> We found that Grx activity was significantly higher in CKD patients compared to control subjects, indicating an oxidized extracellular environment in CKD. Grx levels correlated to interleukin-6 and pentosidine, but not to age or GFR. In dialysis patients with Grx sampling before dialysis start and after 2 years of dialysis, Grx levels increased more in hemodialysis (HD) patients than in peritoneal dialysis patients, indicating an increased oxidative stress imbalance in HD patients. Patients who experienced a stroke or myocardial infarction at any time had a significantly higher increase in Grx during the 2 years of dialysis, compared to patients without stroke or myocardial infarction, indicating a possible association between high Grx levels and a cardiovascular event. <b><i>Conclusion:</i></b> Our pilot study indicates that Grx may be a useful marker for assessing the degree of oxidative stress in CKD, however this needs further investigation in a larger prospective patient cohort.
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