UMLS:C0011881 - FACTA Search

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

Abnormal glucose handling in the proximal tubule may play an important role in the development of diabetic nephropathy. Thus, the present study was designed to examine the effect of high glucose on alpha-methyl-D-glucopyranoside (alpha-MG) uptake and its signaling pathways in the primary cultured rabbit renal proximal tubule cells (PTCs). When PTCs were preincubated with 25 or 50 mM glucose for 4 h, 25 or 50 mM glucose significantly inhibited alpha-MG uptake, while 25 or 50 mM mannitol and L-glucose did not affect. Actinomycin D and cycloheximide did not block the effect of high glucose on alpha-MG uptake. Twenty-five millimoles glucose-induced inhibition of alpha-MG uptake was blocked by mepacrine and AACOCF(3), phospholipase A(2) (PLA(2)) inhibitors. Twenty-five millimoles of glucose, not mannitol or L-glucose, significantly increased the [(3)H]-arachidonic acid (AA) release compared to control. In addition, the 25 mM glucose-induced [(3)H]-AA release was completely blocked by mepacrine or AACOCF(3). Indomethacin, a cyclooxygenase inhibitor, blocked the high glucose-induced inhibition of alpha-MG uptake, although econazole, cytochrome P-450 a epoxygenase inhibitor, and nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, did not. On the other hand, staurosporine and bisindolylmaleimide I, protein kinase C (PKC) inhibitors, blocked 25 mM glucose-induced increase of [(3)H]-AA release and inhibition of alpha-MG uptake. However, neomycin, U 73122, and phospholipase c(PLC) inhibitors did not block the effect of 25 mM glucose on [(3)H]-AA release and alpha-MG uptake. Pretreatment of methoxyverapamil, an L-type Ca(2+) channel blocker, abolished 25 mM glucose-induced increase of [(3)H]-AA release. Indeed, 25 mM glucose increased translocation of cPLA(2) from cytosolic fraction to membrane fraction. In conclusion, the present results demonstrate that high glucose inhibits alpha-MG uptake by the increase of AA release via the activation of PKC.
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PMID:High glucose-induced inhibition of alpha-methyl-D-glucopyranoside uptake is mediated by protein kinase C-dependent activation of arachidonic acid release in primary cultured rabbit renal proximal tubule cells. 1079 10

The development and progression of diabetic nephropathy is dependent on glucose homeostasis and many other contributing factors. In the present study, we examined the effect of nitecapone, an inhibitor of the dopamine-metabolizing enzyme catechol-O-methyl transferase (COMT) and a potent antioxidant, on functional and cellular determinants of renal function in rats with streptozotocin-induced diabetes. Administration of nitecapone to diabetic rats normalized urinary sodium excretion in a manner consistent with the dopamine-dependent inhibition of proximal tubule Na,K-ATPase activity. Hyperfiltration, focal glomerulosclerosis, and albuminuria were also reversed by nitecapone, but in a manner that is more readily attributed to the antioxidant potential of the agent. A pattern of elevated oxidative stress, measured as CuZn superoxide dismutase gene expression and thiobarbituric acid-reactive substance content, was noted in diabetic rats, and both parameters were normalized by nitecapone treatment. In diabetic rats, activation of glomerular protein kinase C (PKC) was confirmed by isoform-specific translocation and Ser23 phosphorylation of the PKC substrate Na,K-ATPase. PKC-dependent changes in Na,K-ATPase phosphorylation were associated with decreased glomerular Na,K-ATPase activity. Nitecapone-treated diabetic rats were protected from these intracellular modifications. The combined results suggest that the COMT-inhibitory and antioxidant properties of nitecapone provide a protective therapy against the development of diabetic nephropathy.
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PMID:Combined antioxidant and COMT inhibitor treatment reverses renal abnormalities in diabetic rats. 1092 41

Considerable evidence suggests that the intrarenal renin-angiotensin system plays an important role in diabetic nephropathy. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (Ang II) receptor blockers (ARBs) can attenuate progressive glomerulosclerosis in disease models and can slow disease progression in humans. Because agents that interfere with Ang II action may decrease glomerular injury without altering glomerular pressures, it has been suggested that Ang II has direct effects on glomerular cells to induce sclerosis independent of its hemodynamic actions. To study nonhemodynamic effects of Ang II on matrix metabolism, many investigators have used cell culture systems. Glucose and Ang II have been shown to produce similar effects on renal cells in culture. For instance, incubation of mesangial cells in high-glucose media or in the presence of Ang II stimulates matrix protein synthesis and inhibits degradative enzyme (e.g., collagenase, plasmin) activity. Glucose and Ang II also can inhibit proximal tubule proteinases. Glucose increases expression of the angiotensinogen gene in proximal tubule cells and Ang II production in primary mesangial cell culture, which indicates that high glucose itself can activate the renin-angiotensin system. The effects of glucose and Ang II on mesangial matrix metabolism may be mediated by transforming growth factor-beta (TGF-beta). Exposure of mesangial cells to glucose or Ang II increases TGF-beta expression and secretion. Their effects on matrix metabolism can be blocked by anti-TGF-beta antibody or ARBs such as losartan, which also prevents the glucose-induced increment in TGF-beta secretion. Taken together, these findings support the hypothesis that the high-glucose milieu of diabetes increases Ang II production by renal, and especially, mesangial cells, which results in stimulation of TGF-beta secretion, leading to increased synthesis and decreased degradation of matrix proteins, thus producing matrix accumulation. This may be an important mechanism linking hyperglycemia and Ang II in the pathogenesis of diabetic nephropathy.
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PMID:Role of angiotensin II in diabetic nephropathy. 1099 97

Alteration of [Ca2+]i by hyperglycemia is implicated in the pathogenesis of diabetic nephropathy. However, the effect of high glucose on Ca2+ regulation in proximal tubule cells is not known. Thus, we examined the mechanisms by which high glucose regulates Ca2+ uptake in primary cultured rabbit renal proximal tubule cells. Glucose increased the Ca2+ uptake in a time- and dose-dependent manner. A stimulatory effect of high glucose on Ca2+ uptake is predominantly observed using 25 mM glucose (high glucose) after 1 h, while 25 mM glucose did not affect cell viability and lactate dehydrogenase release. However, 25 mM mannitol and L-glucose did not affect Ca2+ uptake as compared with controls. Nifedipine and methoxyverapamil (L-type Ca2+ channel blockers) blocked high-glucose-induced stimulation of Ca2+ uptake. High-glucose-induced stimulation of Ca2+ uptake was blocked by pertussis toxin, SQ-22536 (adenylate cyclase inhibitor), myristoylated amide 14-22 (protein kinase A inhibitor), neomycin and U-73122 (phospholipase C inhibitors), and staurosporine and bisindolylmaleimide I (protein kinase C inhibitors). In addition, KN-62 (a Ca2+/calmodulin-dependent protein kinase II inhibitor) and W-7 (a Ca2+/calmodulin antagonist) blocked high-glucose-induced stimulation of Ca2+ uptake. In conclusion, high glucose stimulates the Ca2+ uptake through L-type Ca2+ channels via G-protein-coupled adenylate cyclase/cAMP and phospholipase C/protein kinase C pathways.
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PMID:High glucose stimulates Ca2+ uptake via cAMP and PLC/PKC pathways in primary cultured renal proximal tubule cells. 1117 1

The aim of this study is to investigate the role of the proximal tubule in microalbuminuria in the early stage of diabetic nephropathy. Diabetes was induced in male Sprague-Dawley rats by an injection of streptozotocin (50 mg/kg, i.v.). After 2 weeks, albumin delivery in the proximal tubule was measured using micropuncture and the endocytosis process of FITC-labeled albumin was evaluated with immunoelectron microscopy. Albumin was significantly reabsorbed in the proximal convoluted tubule (PCT) of controls (0.39+/-0.05 ng/min at early PCT to 0.17+/-0.08 at late PCT, P<0.05), whereas albumin reabsorption was inhibited in diabetic rats (0.27+/-0.05 to 0.21+/-0.08). Immunogold study revealed that FITC-albumin was significantly less reabsorbed in endosomes and lysosomes of S1 segments in diabetic rats than in controls (endosome: 1.20+/-0.10 vs 2.16+/-0.15 microm-1, P<0.0001; lysosome: 0.26+/-0.03 vs 0.83+/-0.07, P<0.0001). The expression of megalin, an endocytosis receptor, was decreased at the apical membrane of PCT in diabetic rats. The lipid peroxidation production in the proximal tubule was significantly increased in diabetic rats. In conclusion, albuminuria in early-stage diabetic rats can be partly explained by a decreased albumin endocytosis with reduced megalin expression and with increased lipid peroxidation in the proximal tubule.
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PMID:Reduced albumin reabsorption in the proximal tubule of early-stage diabetic rats. 1168 57

The aim of this study was to determine the influence of metabolic control of diabetes on natriuresis, the effect of natriuretic peptides and renal kallikrein on the kidney and the participation of proximal and distal tubules in natriuresis. The study was done in 41 individuals: 27 IDDM patients and 14 healthy controls. The patients were on insulin only, had normal blood pressure, and were prescribed a standard diabetic diet without sodium or protein restriction. Diabetic patients were assigned to subgroups, depending on the stage of nephropathy and level of metabolic control. Urine collection was done three times daily in all participants. The first collection was done after 500 mg lithium carbonate (p.o.) and was followed by 10 mg amilorid (Midamor, Thomas Morson Pharmaceuticals). The third collection of urine was used to evaluate excretion of cGMP. In addition to sodium, lithium, potassium and creatinine clearances, excretion of renal kallikrein, and levels of microalbuminuria, fructosamine and glycated hemoglobin were also determined. Lithium clearance was used to evaluate tubular sodium transport. The influence of diuretic peptides--ANP and urodilatin, on natriuresis was reflected by urinary cGMP excretion. Function of the kallikrein-kinin system was studied on the basis of excretion of kallikrein. Amilorid was used to test the effect of blocking amiloride-sensitive sodium channels in distal tubules on natriuresis (Tab. 1). A statistically significant decrease in mean lithium clearance was observed in IDDM patients as compared to healthy controls. Creatinine clearance was the same in both groups (Tab. 2). Lower lithium clearance was observed in the subgroup of diabetic patients with "silent" nephropathy. Diabetic patients with "silent" and early nephropathy had significantly higher levels of fractional sodium reabsorption in the proximal tubule when compared with controls (Tab. 3). Moreover, lower daily excretion of kallikrein was observed in patients with stage II nephropathy in comparison to the control group (Tab. 4). Amilorid uptake had no influence on urinary kallikrein. However, natriuresis after amilorid was significantly higher in diabetic patients than in controls. In conclusion, reabsorption in the proximal tubule is increased in patients with "silent" diabetic nephropathy, as revealed by decreased lithium clearance and unchanged creatinine clearance. Hyperactivity of the proximal tubule in stage II and III of diabetic nephropathy results in increased sodium reabsorption in the proximal tubule, as reflected by the increase in fractional sodium reabsorption in this tubule. Amilorid, a distal tubule blocker, reduces distal tubule activity independently of urinary kallikrein excretion. Elevated natriuresis was observed after amilorid without any change in urinary kallikrein excretion.
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PMID:[Regulation of natriuresis in diabetic nephropathy]. 1171 8

Tubulointerstitial disease, a prominent phenomenon in diabetic nephropathy, correlates with decline in renal function. The underlying pathogenic link between chronic hyperglycemia and the development of tubulointerstitial injury has not been fully elucidated, but myofibroblast formation represents a key step in the development of tubulointerstitial fibrosis. RAGE, the receptor for advanced glycation end products (AGEs), induces the expression of TGF-beta and other cytokines that are proposed to mediate the transdifferentiation of epithelial cells to form myofibroblasts. Here we report specific binding of (125)I-AGE-BSA to cell membranes prepared from a rat proximal tubule cell line and show that the binding site was RAGE. AGE exposure induced dose-dependent epithelial-myofibroblast transdifferentiation determined by morphological changes, de novo alpha smooth-muscle actin expression, and loss of epithelial E-cadherin staining. These effects could be blocked with neutralizing Ab's to RAGE or to TGF-beta. Transdifferentiation was also apparent in the proximal tubules of diabetic rats and in a renal biopsy from a patient with type 1 diabetes. The AGE cross-link breaker, phenyl-4,5-dimethylthiazolium bromide (ALT 711) reduced transdifferentiation in diabetic rats in association with reduced tubular AGE and TGF-beta expression. This study provides a novel mechanism to explain the development of tubulointerstitial disease in diabetic nephropathy and provides a new treatment target.
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PMID:Advanced glycation end products cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products (RAGE). 1174 69

The renin-angiotensin system plays an important role in the development of diabetic nephropathy. However, the mechanism of ANG II receptor regulation in the renal proximal tubule in the diabetic condition has not been elucidated. Thus we investigated the signal pathways involved in high-glucose-induced downregulation of ANG II binding in primary cultured renal proximal tubule cells. Twenty-five millimolar glucose, but not mannitol and L-glucose, induced downregulation of the AT(1) receptor (AT(1)R) because of a significant decline in maximal binding with no significant change in the affinity constant. Twenty-five millimolar glucose also decreased AT(1)R mRNA and protein levels. The 25 mM glucose-induced increase in the formation of lipid peroxides was prevented by antioxidants, protein kinase C (PKC) inhibitors, or L-type calcium channel blockers. These agents also blocked 25 mM glucose-induced downregulation of (125)I-ANG II binding. In addition, 25 mM glucose increased transforming growth factor (TGF)-beta1 secretion, and anti-TGF-beta antibody significantly blocked 25 mM glucose-induced downregulation of (125)I-ANG II binding. Furthermore, the 25 mM glucose-induced increase in TGF-beta1 secretion was inhibited by PKC inhibitors, L-type calcium channel blockers, or antioxidants. In conclusion, high glucose may induce downregulation of (125)I-ANG II binding via a PKC-oxidative stress-TGF-beta signal cascade in primary cultured rabbit renal proximal tubule cells.
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PMID:The mechanism of angiotensin II binding downregulation by high glucose in primary renal proximal tubule cells. 1178 36

Diabetic nephropathy is now the commonest cause of end stage renal disease and accounts for 30-40% of all patients requiring renal replacement therapy. Furthermore, the incidence of diabetic nephropathy continues to increase, in part due to the improved survival of type 2 diabetic patients as the cardiovascular mortality in this group declines (Ritz and Stefanski, 1996). Clinically incipient nephropathy is first manifest by the onset of persistent microalbuminuria, after which, overt diabetic nephropathy is heralded by the appearance of persistent proteinuria. Subsequently, there is a progressive decline in glomerular filtration rate (GFR) resulting, within 5 years, in end stage renal disease in 50% of patients (Hasslacher et al., 1989). The pathology of the renal lesions are similar in type I and II diabetes (Taft et al., 1994), although it has been suggested that there is more heterogeneity in type II diabetes (Chihara et al., 1986). Studies analysing structural-functional relationships have demonstrated that the development of proteinuria correlates with the degree of mesangial expansion (Mauer et al., 1984; White and Bilous, 2000). Although diabetic nephropathy was traditionally considered a primarily glomerular disease, it is now widely accepted that the rate of deterioration of function correlates best with the degree of renal tubulointerstitial fibrosis (Mauer et al., 1984, Bohle et al., 1991). This suggests that although in the majority of patients the primary event is a condition manifest by glomerular changes resulting in proteinuria, the long-term outcome is determined by events in the renal interstitium. With the increasing awareness of the importance of these pathological interstitial changes, interest has focused on the role of cells, such as the epithelial cells of the proximal tubule (PTC) or the interstitial myofibroblast, in the initiation of fibrosis. The aim of the present review is to analyse the available data supporting the role for the PTC in orchestrating renal interstitial fibrosis in diabetic nephropathy as a result of glucose-dependent alterations in PTC function. The potential for subsequent effects on PTC-fibroblast cross-talk will also be considered.
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PMID:Diabetic nephropathy: the central role of renal proximal tubular cells in tubulointerstitial injury. 1181 75

Studies using pharmacologic inhibitors have implicated the enzyme aldose reductase in the pathogenesis of albuminuria and diabetic renal disease. However, a clear conclusion is not easily drawn from such studies since these pharmacologic inhibitors have nonspecific properties. To examine further the role of aldose reductase, we have overexpressed the human enzyme in a transgenic rat model. Transgene expression in the kidney was predominantly localized to the outer stripe of the outer medulla, compatible with the histotopography of the straight (S3) proximal tubule. The effect of enzyme overexpression on diabetes-induced renal function and structure was then investigated. Contrary to what may have been anticipated from the previous enzyme inhibition studies, diabetes-induced albuminuria was completely prevented by the overexpression of aldose reductase. No effect of overexpression of aldose reductase on renal structure nor on urinary excretion of beta2-microglobulin and N-acetyl-beta-D-glucosaminidase was observed in this transgenic rat model. In conclusion, our study strongly suggests that multiple roles for aldose reductase may give it a more complex place in diabetic nephropathy than is currently recognized.
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PMID:Prevention of diabetes-induced albuminuria in transgenic rats overexpressing human aldose reductase. 1216 24

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