Early, but Not Advanced, Glomerulopathy Is Reversed by Pancreatic Islet Transplants in Experimental Diabetic Rats: Correlation With Glomerular Extracellular Matrix mRNA Levels

Abstract

In this study, we investigated 1) whether long-term restoration of euglycemia by means of pancreatic islet transplants is capable of preventing and/or reversing renal functional and structural alterations in an experimental model of insulin-deficient diabetes, and 2) whether changes in extracellular matrix (ECM) and cell turnover at the glomerular level and biochemical abnormalities associated with hyperglycemia correlate with the renal outcome after transplantation. Male Lewis rats, rendered diabetic by intravenous injection of streptozotocin, underwent homologous islet transplantation via the portal vein at 2 weeks (study A), at 4 months (study B), and at 8 months (study C) after the induction of diabetes and killed 12 months after transplantation in study A and 4 months after transplantation in studies B and C. Age-matched nondiabetic and untreated diabetic rats were used as control animals and were studied at 4, 8, and 12 months. In the untreated diabetic animals, metabolic derangement was associated with increased erythrocyte polyol and fructose levels, tail-tendon content of advanced glycation end products (AGEs), total proteinuria, albuminuria, kidney weight, and mean glomerular volume as well as with marked glomerular and extraglomerular lesions. Glomerular gene expression for the ECM components fibronectin and collagen IV and for TGF-beta was also increased, whereas glomerular cell proliferation was unaffected by diabetes. In study A, changes in renal function and structure observed in diabetic rats at 12 months were completely prevented by successful islet transplants. In study B, all functional and structural abnormalities detected in diabetic rats at 4 months of disease duration were virtually reversed by 4 months of euglycemia in transplanted animals, whereas they progressed further in untreated diabetic rats. In study C, the course of functional and structural changes observed in untreated diabetic rats was not reversed by islet transplantation. Likewise, tissue AGE accumulation and particularly upregulation of glomerular ECM and transforming growth factor (TGF)-beta gene expression, which are believed to play a role in the pathogenesis of altered renal function and structure in diabetes, were normalized in transplanted rats from study A and study B, but not in those from study C. These experiments show that restoration of euglycemia by islet transplants is capable of preventing experimental diabetic glomerulopathy and reversing early changes in renal function and structure induced by diabetes. In a later phase of the disease, when glomerular matrix gene expression becomes independent of hyperglycemia, possibly because of the persistent increase in tissue AGE accumulation, metabolic control is not capable of reversing renal abnormalities.

Deletion of p66Shc Longevity Gene Protects Against Experimental Diabetic Glomerulopathy by Preventing Diabetes-Induced Oxidative Stress

“…Since glomeruli only account for a small percentage of whole kidney cortex (29), their content of these matrix proteins was verified by immunohistochemistry, which showed higher glomerular levels of both fibronectin (Fig. 4A-D) and collagen IV (Fig.…”

Increased glomerular cell (podocyte) apoptosis in rats with streptozotocin-induced diabetes mellitus: role in the development of diabetic glomerular disease

“…This is at variance with glomerular cell proliferation, which was not significantly affected in this experimental animal model of diabetes [7,30]. Topographical localisation and double immunohistochemistry also indicated that podocytes are the predominant apoptosing cells under these conditions, although endothelial and mesangial cells are also lost.…”

“…; Sigma Chemical, St Louis, MO, USA) [29]. Insulin-treated diabetic rats and rats showing spontaneous reversal of diabetes [30] served as control for streptozotocin effect. Rats were studied for 7 days and for 2, 4 and 6 months after initiation of the study (n=6 for both groups at each time point).…”

The diabetic milieu modulates the advanced glycation end product-receptor complex in the mesangium by inducing or upregulating galectin-3 expression.

“…Adult (aged 8-10 weeks) male Sprague-Dawley rats (Harlan Nossan, Milan, Italy) were divided into nondiabetic (n = 22) and diabetic (n = 22) groups. Rats were made diabetic by a single injection (via the caudal vein) of streptozotocin at a dose of 60 mg/kg body wt in citrate buffer (pH 4.5) (20). The animals were housed and cared in keeping with European Community regulations, and they received water and food ad libitum.…”