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Query: UMLS:C0011881 (diabetic nephropathy)
 10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diabetes mellitus contributes greatly to morbidity, mortality, and overall health care costs. In major part, these outcomes derive from the high incidence of progressive kidney dysfunction in patients with diabetes making diabetic nephropathy a leading cause of end-stage renal disease. A better understanding of the early dysfunctions observed in the diabetic kidney may permit the development of new strategies to prevent diabetic nephropathy. This review proposes a "tubulo-centric" view of glomerular function in early type I diabetes mellitus. The following are particularly discussed (1) the primary role of an increase in reabsorption by the proximal tubule in early glomerular hyperfiltration, (2) the role of sodium-glucose cotransport and tubular growth under these conditions, and (3) the primary role of reabsorption by the proximal tubule for the paradoxical relationship between dietary salt and glomerular filtration rate. Finally, an outline is presented of potential therapeutic implications for the prevention of diabetic kidney disease.
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PMID:Glomerular hyperfiltration and the salt paradox in early [corrected] type 1 diabetes mellitus: a tubulo-centric view. 1253 55

Gene therapy has the potential to provide a therapeutic strategy for numerous renal diseases such as diabetic nephropathy, chronic rejection, Alport syndrome, polycystic kidney disease, and inherited tubular disorders. In previous studies using cationic liposomes or adenoviral or retroviral vectors to deliver genes into the kidney, transgene expression has been transient and often associated with adverse host immune responses, particularly with the use of adenoviral vectors. The unique properties of recombinant adeno-associated viral (rAAV) vectors permit long-term stable transgene expression with a relatively low host immune response. The purpose of the present study was to evaluate gene expression in the rat kidney after intrarenal arterial infusion of a rAAV (serotype 2) vector encoding green fluorescence protein (GFP) induced by a cytomegalovirus-chicken beta-actin hybrid promoter. The left kidney of experimental animals was treated with either saline or transduced with rAAV2-GFP (0.125 ml/100 g body wt, 1 x 10(10)/ml infectious units) through the renal artery. A time-dependent expression of GFP was observed in all kidneys injected with rAAV2-GFP, with maximal expression observed at 6 wk posttransduction. The expression of GFP was restricted to cells in the S(3) segment of the proximal tubule and intercalated cells in the collecting duct, the latter identified by co-localization with H(+)-ATPase. No transduction was observed in the glomeruli or the intrarenal vasculature. These studies demonstrate successful transgene expression in tubular epithelial cells, specifically in the S(3) segment of the proximal tubule and intercalated cells, after intrarenal administration of a rAAV vector and provide the impetus for further studies to exploit its use as a tool for gene therapy in the kidney.
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PMID:Gene delivery in renal tubular epithelial cells using recombinant adeno-associated viral vectors. 1266 Mar 29

Advanced glycation end products (AGE) are filtered by glomeruli and reabsorbed and metabolized by proximal tubule cells (PTC). In renal failure, decreased renal AGE metabolism likely accounts for the accumulation in serum that is related to uremic complications. In diabetes, AGE generation is increased, and the handling mechanisms in PTC are likely associated with the pathogenesis of tubulointerstitial injury. It is therefore important to clarify the mechanisms of the AGE metabolism to develop a strategy for removing AGE in uremia and to elucidate the pathogenesis of diabetic nephropathy. To this end, this study focused on the molecular analysis of megalin, a multi-ligand endocytic receptor, in PTC. AGE uptake analysis was performed using the rat yolk sac-derived L2 cell line system established for the analysis of megalin's endocytic functions. The cells mediated specific internalization and degradation of AGE, which were significantly blocked by anti-megalin IgG, indicating that megalin is involved in the cellular processes. However, cell surface AGE-binding assays and ligand blot analysis revealed no evidence that megalin is a direct AGE receptor. Affinity chromatography and ligand blot analysis originally revealed that 200-kD and 400-kD proteins in the cells bind to AGE and the 200-kD protein to megalin in a Ca(2+)-dependent manner. The binding of megalin with the 200-kD protein was suppressed by receptor-associated protein (RAP), a ligand for megalin. In conclusion, megalin functions for endocytosis of AGE via an indirect mechanism. L2 cells express novel AGE-binding proteins, one of which may interact with megalin.
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PMID:Role of megalin in endocytosis of advanced glycation end products: implications for a novel protein binding to both megalin and advanced glycation end products. 1270 83

The kidney plays an important role in protein metabolism. The albumin reabsorption in the proximal tubule is disturbed in the early stage of diabetic nephropathy. We evaluated the effects of angiotensin converting enzyme inhibitor (ACEI) and angiotensin III type 1 receptor blocker (ARB) on albumin reabsorption and expression of megalin, an endocytosis receptor for albumin, in proximal tubules of streptozotocin (STZ)-induced diabetic-rats. Diabetic rats at the second week after STZ injection were treated with quinapril (3 mg/kg/day) or candesartan (0.05 mg/kg/day) for 2 weeks. The tubular reabsorption of fluorescein isothiocyanate (FITC)-labeled albumin was evaluated by immunogold electron microscopy, and megalin expression was investigated by immunohistochemistry and Western blotting. Reabsorption of FITC-labeled albumin and megalin expression were prominently inhibited in the proximal convoluted tubules of diabetic rats compared to the controls. Both quinapril and candesartan restored albumin reabsorption in the proximal tubule due to normalization of megalin expression. Urinary albumin excretion was significantly reduced by both ACEI and ARB treatment. Angiotensin II infusion decreased megalin expression and albumin reabsorption in the proximal tubule. In conclusion, angiotensin II blockade restored albumin reabsorption via amelioration of megalin expression in the proximal tubules of early stage diabetic rats.
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PMID:Angiotensin II blockade restores albumin reabsorption in the proximal tubules of diabetic rats. 1288 33

1. Calcium regulation has been reported to be associated with the development of diabetic nephropathy. Thus, changes in Ca2+ uptake induced by ATP, an important regulator of Ca2+ uptake, in the diabetic condition and related signal pathways were examined in primary cultures of rabbit renal proximal tubule cells (PTC). 2. Under low (5 mmol/L) glucose conditions, 10-4 mol/L ATP inhibited Ca2+ uptake early on (< 30 min), whereas Ca2+ uptake was stimulated at later time points (> 2 h). However, under high (25 mmol/L) glucose conditions, ATP stimulated both the early and late uptake of Ca2+. 3. The adenylate cyclase inhibitor SQ 22536, the protein kinase (PK) A inhibitor PKI amide 14-22, Rp-cAMP, staurosporine, bisindolylmaleimide I and H-7 (PKC inhibitors) blocked the change in ATP effect on Ca2+ uptake in the presence of 25 mmol/L glucose. However, none one of these drugs blocked the effect of ATP on Ca2+ uptake in the presence of 5 mmol/L. 4. At 25 mmol/L, glucose increased cAMP content and PKC activity, whereas ATP had no effect on either parameter. 5. In conclusion, high glucose levels alter ATP-induced Ca2+ uptake via cAMP and PKC pathways in the PTC.
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PMID:Effect of ATP on Ca2+ uptake in the presence of high glucose in renal proximal tubule cells. 1294 Aug 90

We now know that the rate of progression of diabetic nephropathy, like all progressive renal disease, correlates with the degree of corticointerstitial fibrosis. Therefore, much interest has focused on the contribution of the resident cells in the renal cortex to this process. This article reviews the evidence that the epithelial cells of the proximal tubule are major players in orchestrating events in the corticointerstitium in diabetic nephropathy. More specifically, it addresses their role in extracellular matrix turnover, generation of cytokines, and recruitment of inflammatory cells, as well as examining the concept that they are the source of the interstitial myofibroblasts, which are the principal mediators of the fibrotic process.
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PMID:The role of renal proximal tubular cells in diabetic nephropathy. 1461 46

Pathological alterations in glomerular mesangial cells play a critical role in the development of diabetic nephropathy, the leading cause of end-stage renal disease. Molecular mechanisms mediating such alterations, however, remain to be fully understood. The present study first examined the effect of high glucose on the mRNA expression profile in rat mesangial cells using cDNA microarray. Based on variation-weighted criteria and with a false discovery rate of 4.3%, 459 of 17,664 cDNA elements examined were found to be upregulated and 151 downregulated by exposure to 25 mM d-glucose for 5 days. A large number of differentially expressed genes belonged to several functional categories, indicating high glucose had a profound effect on mesangial cell proliferation, protein synthesis, energy metabolism, and, somewhat unexpectedly, protein sorting and the cytoskeleton. Interestingly, several thiol antioxidative genes (glutathione peroxidase 1, peroxiredoxin 6, and thioredoxin 2) were found by microarray and confirmed by real-time PCR to be upregulated by high glucose. These changes suggested that the oxidative stress known to be induced in mesangial cells by high glucose might be buffered by upregulation of the thiol antioxidative pathway. Upregulation of thiol antioxidative genes also occurred in high-glucose-treated human mesangial cells and in glomeruli isolated from rats after 1 wk of streptozotocin-induced diabetes, but not in human proximal tubule cells. High glucose slightly increased lipid peroxidation and decreased the amount of reduced thiols in rat and human mesangial cells. Disruption of the thiol antioxidative pathway by two different thiol-oxidizing agents resulted in a three- to fivefold increase in high-glucose-induced lipid peroxidation. In summary, the present study provided a global view of the short-term effect of high glucose on mesangial cells at the level of mRNA expression and identified the upregulation of the thiol antioxidative pathway as an adaptational response of mesangial cells to high glucose.
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PMID:Effect of high glucose on gene expression in mesangial cells: upregulation of the thiol pathway is an adaptational response. 1503 83

Oxidative stress plays an important role in the pathogenesis of renal diseases such as diabetic nephropathy. The metabolism of excessive intracellular glucose may involve a number of processes. One consequence of excessive intracellular glucose levels is an increased rate of oxidative phosphorylation under hyperglycemic conditions, whereas another consequence is an increase in the metabolism of glucose to sorbitol by aldose reductase. In addition, hyperglycemia may result in the activation of NADPH oxidase, the production of superoxide anion, and hydrogen peroxide (H2O2). In this report, we investigate the mechanisms responsible for the H2O2 production that occurs as the consequence of hyperglycemia and the effect of H2O2 on the activity of the Na+/glucose cotransport system (SGLT) in primary cultures of renal proximal tubule cells (PTCs). When primary PTCs were cultured in the presence of high glucose, one consequence was that the Na+/glucose cotransport system was inhibited, as indicated by uptake studies utilizing alpha-methyl-D-glucoside (alpha-MG), a nonmetabolizable analog of D-glucose. Pretreatment of the cultures with either 1) aminoguanidine or pyridoxamine [inhibitors of the accumulation of advanced glycation end products (AGEs)], 2) rotenone (an inhibitor of the mitochondrial electron transport chain), or 3) apocynin or diphenylene iodonium (DPI; inhibitors of NADPH oxidase) blocked the observed changes that occurred as a consequence of the incubation of the PTCs with high glucose. Included among these changes were the observed increase in H2O2 levels, as well as an increase in lipid peroxide production, and a decrease both in the activity of catalase and in the level of glutathione (GSH), endogenous antioxidants. The high glucose-induced decrease in the level of the Na+/glucose cotransporter was similarly prevented by either aminoguanidine, rotenone, or apocynin. Thus the inhibitory effect of high glucose on both the level of the Na+/glucose cotransport system and the activity of the Na+/glucose cotransport system can be explained, at least in part, as being due to the effects of the H2O2, the consequent formation of AGEs, the increase in mitochondrial metabolism, and in NADPH oxidase activity in the PTCs. Other related changes observed in the PTCs that could be reversed by treatment with either aminoguanidine, pyridoxamine, rotenone, apocynin, or DPI included an increase in transforming growth factor-beta1 secretion and the activation of the NF-kappaB signal transduction pathway.
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PMID:High glucose-induced oxidative stress inhibits Na+/glucose cotransporter activity in renal proximal tubule cells. 1559 43

Far from being bystanders in diabetic nephropathy, changes in the proximal tubule are important for the development of progressive diabetic kidney disease. The proximal tubule is uniquely susceptible to a variety of metabolic and hemodynamic factors associated with diabetes. Renal function and prognosis correlate better with structural lesions in the tubuli and cortical interstitium than with classical glomerular changes of diabetic nephropathy. The proximal tubules show a variety of poorly characterized changes, which have led to the notion that tubular damage represents a "final common pathway" for proteinuric renal injury. However, tubular hypertrophy, reduced organic ion transport, and other tubular changes reviewed in this paper, are already apparent before the onset of proteinuria in diabetes. Indeed, increased tubuloglomerular feedback and defective uptake and lysosomal processing may independently contribute to hyperfiltration and urinary protein loss, respectively. This finding does not mean that glomerular or vascular dysfunction do not contribute to progressive nephropathy. However, although subdividing the nephron for the purposes of analysis and scientific discovery may be useful, the interactions between tubule, glomerulus, and interstitium are likely key to the understanding of complex disorders such as diabetic nephropathy. From this "holonephric" point of view, an understanding of the changes in the diabetic tubule forms an important component to the understanding of kidney disease in diabetes.
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PMID:Tubular changes in early diabetic nephropathy. 1582 53

Increased GLUT2 gene expression in the renal proximal tubule of diabetic rats is an adaptive condition, which may be important in the diabetic nephropathy development. We investigated the effects of insulin treatment upon the renal GLUT2 overexpression of diabetic rats. Acute treatment, surprisingly, induced a rapid further increase in GLUT2 mRNA content. Twelve hours after insulin injection, GLUT2 mRNA was twice the value of saline-injected rats (P<0.001), when GLUT2 protein remained unchanged. In response to short-term treatment, both GLUT2 mRNA and protein were increased in 1-day treated rats (P<0.05 versus saline-injected), decreasing after that, and reaching, within 6 days, values close to those of non-diabetic rats. Concluding, insulin treatment induced: initially, an additional upregulation of GLUT2 gene expression, involving posttranscriptional modulation; thereafter, downregulation of GLUT2 expression, which returns to non-diabetic levels. The former may be related to increased insulin concentration, the latter may be due to glycemic control.
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PMID:Acute and short-term insulin-induced molecular adaptations of GLUT2 gene expression in the renal cortex of diabetic rats. 1586 38


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