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)

Sex differences in the incidence and progression of renal diseases suggest a protective role for estrogen. This study examined the role of estrogen receptor alpha (ERalpha)-mediated events in normal and diabetic renal and glomerular growth. Wild-type and ERalpha-null mice (ERKO) were observed over 2 wk of streptozocin-induced diabetes. Blood glucose was monitored, and insulin was given daily to maintain levels of 250-350 mg/dl. Body weight, kidney weight, glucose, insulin, renal transforming growth factor-beta(1), and glomerular area were examined for effects of sex, genotype, and diabetes. Genotype had no effect on glomerular or renal size in male mice regardless of metabolic state. Nondiabetic female ERKO mice had kidney weights approaching those of wild-type males and much greater than those of wild-type females (0.15 +/- 0.04 vs. 0.11 +/- 0.04 g; P < 0.001). When only diabetic mice were studied, sex and/or genotype showed no effect on renal weight. Diabetic female ERKO mice had smaller glomerular areas than wild types (2,799 +/- 159 vs. 3,409 +/- 187 microm(2); P = 0.01). Glomerular areas were similar in diabetic wild-type and ERKO males (3,020 +/- 199 vs. 3,406 +/- 176 microm(2)). Transforming growth factor-beta(1) levels, expressed as picograms per milligram total protein, were similar in diabetic wild-type and ERKO males (1.0 +/- 0.6 vs. 0.9 +/- 0.6). In diabetic females, wild types had significantly higher levels of this growth factor than ERKO mice (3.8 +/- 0.7 vs. 1.1 +/- 0.6; P = 0.005). ERalpha-mediated processes influence normal and diabetic renal and glomerular size, but only in female mice. These data do not support a protective role for ERalpha-mediated events in diabetic nephropathy.
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PMID:Estrogen receptor alpha-mediated events promote sex-specific diabetic glomerular hypertrophy. 1514 72

The molecular events associated with acute and chronic exposure of mesangial cells (MC) to hyperglycemia were evaluated. We found that, unlike high glucose (HG) and Amadori adducts, advanced glycation end products (AGE) and transforming growth factor-beta (TGF-beta) induced p21waf expression and accumulation of MC in G0/G1. TGF-beta1 blockade inhibited AGE-mediated collagen production but only partially affected AGE-induced p21waf expression and cell-cycle events, indicating that AGE by binding to AGE receptor (RAGE) per se could control MC growth. Moreover, AGE and TGF-beta treatment led to the activation of the signal transduction and activators of transcription (STAT)5 and the formation of a STAT5/p21SIE2 complex. The role of STAT5 in AGE- and TGF-beta-mediated p21waf expression and growth arrest, but not collagen production, was confirmed by the expression of the dominant negative STAT5 (DeltaSTAT5) or the constitutively activated STAT5 (1*6-STAT5) constructs. Finally, in p21waf-/- fibroblasts both AGE and TGF-beta failed to inhibit cell-cycle progression. A potential in vivo role of these mechanisms was sustained by the increasing immunoreactivity for the activated STAT5 and p21(waf) in kidney biopsies from early to advanced stage of diabetic nephropathy. Our data indicate that AGE- and TGF-beta-mediated signals, by converging on STAT5 activation and p21waf expression, may regulate MC growth.
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PMID:RAGE- and TGF-beta receptor-mediated signals converge on STAT5 and p21waf to control cell-cycle progression of mesangial cells: a possible role in the development and progression of diabetic nephropathy. 1518 Sep 53

Amadori-modified glycated albumin stimulates extracellular matrix and transforming growth factor-beta (TGF-beta) expression in cultured mesangial cells. Smad proteins transduce the TGF-beta-mediated signal, and Smad-binding CAGA sequences are present in the plasminogen activator inhibitor-1 (PAI-1) promoter. This study examined whether glycated albumin induces PAI-1 transcription in human mesangial cells (HMC) through Smad-binding sites in the PAI-1 promoter. Quiescent HMC were exposed to 200 microg/ml bovine serum albumin (BSA) or glycated BSA (Gly-BSA) for 12-72 h. At 24 h, Gly-BSA stimulated TGF-beta1 and PAI-1 mRNA expression in HMC to 1.8 and 3.2 times that in the BSA-treated control cells. Gly-BSA also activated the PAI-1 promoter luciferase activity 2.3-fold. Gly-BSA-treated cells enhanced Smad2 and Smad3 protein levels 2.5 times the control levels in the nuclei. An electrophoretic mobility shift assay performed using CAGA sequences as a probe showed that Gly-BSA increased DNA/protein complexes. When nuclear extracts were preincubated with 100-fold molar excess of unlabeled CAGA oligonucleotide, the formation of complex was prevented. The DNA-binding protein was shown to be Smad3 by antibody supershift. Transfection of phosphorothioate CAGA oligonucleotide, a CAGA antisense analog, inhibited Gly-BSA-induced PAI-1 mRNA expression. Cotransfection of phosphorothioate CAGA oligonucleotides with PAI-1 reporter vector also blocked Gly-BSA-induced PAI-1 promoter luciferase activity. These results indicate that Gly-BSA increases DNA binding activity of Smad3 and that it stimulates PAI-1 transcription through Smad-binding CAGA sequences in the PAI-1 promoter in HMC. Thus progression of diabetic nephropathy may be promoted by PAI-1 upregulation mediated by the glycated albumin-induced Smad/DNA interactions.
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PMID:Glycated albumin activates PAI-1 transcription through Smad DNA binding sites in mesangial cells. 1519 28

The protective factor of female gender appears to be lost in diabetes; the incidence of diabetes and its complications, including diabetic nephropathy, are equal in women and men. This study examined the effects of estrogen deficiency by ovariectomy (OVX) and replacement with 17beta-estradiol (OVX+E2) on renal function and pathology in the nondiabetic (ND) and streptozotocin (STZ)-induced diabetic (D) rat kidneys for 12 wk. Diabetes was associated with an increase in urine albumin excretion (UAE; ND, 0.39 +/- 0.03; D, 5.9 +/- 0.8 mg/day; P < 0.001), decrease in creatinine clearance (CrCl; ND, 0.69 +/- 0.03; D, 0.43 +/- 0.09 mg x min(-1) x 100 g body wt(-1); P < 0.05), increase in the index of glomerulosclerosis [GSI; ND, 0.01 +/- 0.01; D, 0.15 +/- 0.04 arbitrary units (AU); P < 0.01], tubulointerstitial fibrosis (TIFI; ND, 0.04 +/- 0.04; D, 0.68 +/- 0.2 AU; P < 0.01), and transforming growth factor-beta (TGF-beta) protein expression (ND, 0.61 +/- 0.02; D, 1.25 +/- 0.07 AU; P < 0.01). In the D group, the severity of these changes was augmented with OVX (UAE, 8.1 +/- 0.6 mg/day; CrCl, 0.40 +/- 0.04 mg x min(-1) x 100 g body wt(-1); GSI, 0.29 +/- 0.04 AU; TIFI, 0.90 +/- 0.06 AU; TGF-beta, 1.26 +/- 0.10 AU), whereas E2 replacement attenuated these changes (UAE, 6.3 +/- 0.8 mg/day; CrCl, 0.66 +/- 0.03 mg x min(-1) x 100 g body wt(-1); GSI, 0.06 +/- 0.02 AU; TIFI, 0.36 +/- 0.08 AU; TGF-beta, 0.57 +/- 0.08 AU). We conclude that E2 deficiency increases the severity of renal disease in a diabetic animal model and that E2 replacement is renoprotective by attenuating the decline in renal function and pathology associated with diabetes.
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PMID:17beta-Estradiol replacement improves renal function and pathology associated with diabetic nephropathy. 1545 92

Diabetic nephropathy is continuing to rise in incidence, despite awareness of tight glycemic control and blood pressure. The identification that matrix accumulation is driven by transforming growth factor-beta (TGF-beta) has led to a concerted effort to apply antifibrotic strategies for this disorder. Recent studies have not only demonstrated the beneficial effects of blocking TGF-beta on matrix accumulation but have also found that blocking TGF-beta may have important hemodynamic effects that are relevant to diabetic complications. In this article, we review the latest knowledge regarding the role of TGF-beta in diabetic kidney disease and discuss available and novel therapeutic approaches. The role of a novel antifibrotic drug, pirfenidone, may have important clinical relevance to diabetic nephropathy.
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PMID:Transforming growth factor-beta: a clinical target for the treatment of diabetic nephropathy. 1553 10

Pigment epithelium-derived factor (PEDF) is a potent angiogenic inhibitor. Previous studies have shown that decreased ocular levels of PEDF are associated with diabetic retinopathy. However, the implication of PEDF expression in diabetic nephropathy has not been revealed. In the present study, we demonstrated for the first time that the expression of PEDF was decreased at both the mRNA and protein levels in the kidney of diabetic rats, whereas transforming growth factor-beta (TGF-beta) and fibronectin levels were increased in the same diabetic kidneys. As shown by immunohistochemistry, the decrease of PEDF expression occurs primarily in the glomeruli. In vitro studies showed that high concentrations of glucose significantly decreased PEDF secretion in primary human glomerular mesangial cells (HMCs), suggesting that hyperglycemia is a direct cause of the PEDF decrease in the kidney. Toward the function of PEDF, we showed that PEDF blocked the high-glucose-induced overexpression of TGF-beta, a major pathogenic factor in diabetic nephropathy, and fibronectin in primary HMCs, suggesting that PEDF may function as an endogenous inhibitor of TGF-beta expression and fibronectin production in glomeruli. Therefore, decreased expression of PEDF in diabetic kidneys may contribute to extracellular matrix overproduction and the development of diabetic nephropathy.
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PMID:Decreased expression of pigment epithelium-derived factor is involved in the pathogenesis of diabetic nephropathy. 1561 35

In diabetes, mesangial cell proliferation and extracellular matrix expansion are critical components in the development of glomerulosclerosis. We reported that diabetes alters the activity of the kallikrein-kinin system and that these alterations contribute to the development of diabetic nephropathy. The present study examined the influence of streptozotocin-induced diabetes on the renal expression of bradykinin (BK) B2 receptors (B2KR), connective tissue growth factor (CTGF), transforming growth factor-beta (TGF-beta), and TGF-beta type II receptor (TGF-betaRII) and assessed the signaling mechanisms through which B2KR activation may promote glomerular injury. Eight weeks after the induction of diabetes, renal mRNA levels of B2KR, CTGF, and TGF-beta as well as protein levels of CTGF and TGF-betaRII were measured in control (C), diabetic (D), and insulin-treated diabetic (D+I) rats. Renal B2KR and TGF-beta mRNA levels expressed relative to beta-actin mRNA levels and CTGF and TGF-betaRII protein levels were significantly increased in D and D+I rats compared with C rats (P < 0.03, n = 5). To assess the contribution of B2KR activation on modulating the expression of CTGF, TGF-betaRII, and collagen I, mesangial cells (MC) were treated with BK (10(-8) M) for 24 h and CTGF and TGF-betaRII protein levels were measured by Western blots and collagen I mRNA levels were measured by RT-PCR. A two- to threefold increase in CTGF and TGF-betaRII protein levels was observed in response to BK stimulation (P < 0.001, n = 6). In addition, a marked increase in collagen I mRNA levels was observed in response to BK stimulation. Treatment of MC with BK (10(-8) M) for 5 min significantly increased the tyrosine phosphorylation of p60src kinase and of p42/p44 MAPK (P < 0.05, n = 4). Inhibition of src kinase by PP1 (10 microM) inhibited the increase in p42/p44 MAPK activation in response to BK. Finally, to determine whether BK stimulates CTGF, TGF-betaRII, and collagen I expression via activation of MAPK pathways, MC were pretreated with an inhibitor of p42/p44 MAPK (PD-98059) for 45 min, followed by BK (10(-8) M) stimulation for 24 h. Selective inhibition of p42/p44 MAPK significantly inhibited the BK-induced increase in CTGF, TGF-betaRII, and collagen I levels. These findings are the first to demonstrate that BK regulates the expression of CTGF, TGF-betaRII, and collagen I in MC and provide a mechanistic pathway through which B2KR activation may contribute to the development of diabetic nephropathy.
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PMID:Mechanisms through which bradykinin promotes glomerular injury in diabetes. 1569 59

We have previously reported that N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), which is a tetrapeptide hydrolyzed by ACE, inhibits the transforming growth factor-beta (TGF-beta)-induced expression of extracellular matrix proteins via inhibition of the Smad signaling in human mesangial cells. To test in vivo the antifibrotic efficacy of Ac-SDKP, we examined whether long-term Ac-SDKP treatment can prevent renal insufficiency and glomerulosclerosis in diabetic db/db mice. Diabetic db/db mice or nondiabetic db/m mice were treated with Ac-SDKP for 8 weeks using osmotic minipumps. The treatment with Ac-SDKP increased plasma Ac-SDKP concentrations by approximately threefold in both groups but did not affect the blood glucose levels. Histologically, the increased glomerular surface area, mesangial matrix expansion, and overproduction of extracellular matrix proteins in db/db mice were significantly inhibited by Ac-SDKP. Furthermore, Ac-SDKP treatment normalized the increased plasma creatinine value in db/db mice, whereas the albuminuria in Ac-SDKP-treated db/db mice was somewhat decreased as compared with nontreated db/db mice, although the difference was not statistically significant. In addition, the nuclear translocation of Smad3 was inhibited by Ac-SDKP. These results demonstrate that long-term Ac-SDKP treatment ameliorates renal insufficiency and glomerulosclerosis in db/db mice via inhibition of TGF-beta/Smad pathway, suggesting that Ac-SDKP could be useful in the treatment of diabetic nephropathy.
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PMID:N-acetyl-seryl-aspartyl-lysyl-proline prevents renal insufficiency and mesangial matrix expansion in diabetic db/db mice. 1573 63

The present study was performed to investigate the effects of the antiallergic drug tranilast on the development of diabetic nephropathy in streptozotocin (50 mg/kg)-induced diabetic spontaneously hypertensive rats (SHR). Diabetic SHR were given standard chow or chow containing tranilast at a dose of 1400 mg/kg for 24 weeks. The effects of tranilast on urinary albumin excretion, mesangial expansion, expression of transforming growth factor-beta (TGF-beta) and type I collagen mRNAs, number of anionic sites on the glomerular basement membrane (GBM), and urinary TGF-beta and 8-hydroxy-2'-deoxyguanosine (8-OHdG) excretion were assessed. Tranilast did not affect the blood glucose concentration or blood pressure in diabetic SHR. Urinary albumin excretion rate and creatinine clearance were markedly increased in diabetic SHR. Tranilast treatment decreased albuminuria and hyperfiltration. Tranilast inhibited the diabetes-induced expansion of mesangial and tuft areas, as well as the increase in urinary TGF-beta and 8-OHdG excretion, loss of anionic sites of GBM, and overexpression of TGF-beta as determined immunohistochemically. The levels of TGF-beta and type I collagen mRNA expression were increased in the renal cortex in untreated diabetic SHR at 24 weeks, as determined by real-time quantitative polymerase chain reaction. Tranilast treatment inhibited the up-regulation of TGF-beta and type I collagen mRNA expression by 65 and 36%, respectively, in diabetic SHR. In conclusion, tranilast decreased albuminuria by suppressing glomerular hyperfiltration, mesangial expansion, and loss of the charge barrier via regulation of extracellular matrix gene expression and oxidative stress. Tranilast may be clinically useful in the treatment of diabetic nephropathy.
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PMID:Tranilast prevents the progression of experimental diabetic nephropathy through suppression of enhanced extracellular matrix gene expression. 1585 46

Nephropathy is a major complication of diabetes. Alterations of mesangial cells have traditionally been the focus of research in deciphering molecular mechanisms of diabetic nephropathy. Injury of podocytes, if recognized at all, has been considered a late consequence caused by increasing proteinuria rather than an event inciting diabetic nephropathy. However, recent biopsy studies in humans have provided evidence that podocytes are functionally and structurally injured very early in the natural history of diabetic nephropathy. The diabetic milieu, represented by hyperglycemia, nonenzymatically glycated proteins, and mechanical stress associated with hypertension, causes downregulation of nephrin, an important protein of the slit diaphragm with antiapoptotic signaling properties. The loss of nephrin leads to foot process effacement of podocytes and increased proteinuria. A key mediator of nephrin suppression is angiotensin II (ANG II), which can activate other cytokine pathways such as transforming growth factor-beta (TGF-beta) and vascular endothelial growth factor (VEGF) systems. TGF-beta1 causes an increase in mesangial matrix deposition and glomerular basement membrane (GBM) thickening and may promote podocyte apoptosis or detachment. As a result, the denuded GBM adheres to Bowman's capsule, initiating the development of glomerulosclerosis. VEGF is both produced by and acts upon the podocyte in an autocrine manner to modulate podocyte function, including the synthesis of GBM components. Through its effects on podocyte biology, glomerular hemodynamics, and capillary endothelial permeability, VEGF likely plays an important role in diabetic albuminuria. The mainstays of therapy, glycemic control and inhibition of ANG II, are key measures to prevent early podocyte injury and the subsequent development of diabetic nephropathy.
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PMID:From the periphery of the glomerular capillary wall toward the center of disease: podocyte injury comes of age in diabetic nephropathy. 1591 82

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