Evidence for a role of TGFp in diabetic kidney disease

In vitro, TGF-p modulates ECM production in glomerular mesangial and epithelial cells.160161 In addition, TGF-p inhibits the synthesis of collagenases and stimulates the production of metalloproteinase inhibitors, an effect which could lead to reduced degradation of ECM and hence ECM accumulation.162,163 Furthermore, high glucose concentrations increase TGF-p1 mRNA expression in renal cells,157,159 and stimulate TGF-p mRNA expression and bioactivity, cellular hypertrophy, and collagen transcription in proximal tubules,159 providing in vitro evidence for a role of TGF-p in the development of diabetic kidney disease. In different models of experimental type 1 diabetes, increased glomerular TGF-p1 mRNA has been found early in the course of diabetes-induced renal growth.164,165 In addition, in long-term STZ-diabetic rats, a sustained increase in glomerular TGF-p1 mRNA has been described.157 Recently, changes in the whole TGF-p system (i.e., TGF-p1, TGF-p2, TGF-p3 isoforms and TGF-p type RI, RII, and TGF-p type III receptors) have been studied rigorously in acute and chronic diabetes.158 The TGF-p1 and TGF-p2 isoforms and the TGF-p type RII were the most responsive elements within the glomerulus and the tubules in response to diabetes induction.158 The changes in TGF-p1 in diabetes seem to be compartmentalized in the kidney, whereas glomerular TGF-p2 and TGF-p type RII are both upregulated in diabetes, suggesting that fibrogenic signalling is increased.158 In diabetic subjects with nephropathy, an increased TGF-p immunostaining has been described both in glomeruli166,167 and in tubulointerstitium,166 but this finding has also been reported in other renal diseases characterized by accumulation of ECM.166 Further, a positive correlation between TGF-p, fibronectin and plasminogen activator inhibitor-1 levels in glomeruli and tubulointerstitium was found.166 By measuring the renal arteriovenous TGF-pi gradient in type 2 diabetic patients, an increased renal production of TGF-P1 has been shown.168 Type 2 diabetic subjects also present with increased urinary TGF-P1 levels168,169 which correlate with UAE.169 Taken together, these experimental and clinical studies indicate that the glucose-induced rise in renal TGF-p is responsible for some of the renal changes that precede the development of diabetic kidney disease.

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