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Kidney International


Background. Previously, we showed the expression of a unique sulfonylurea receptor (SUR) and its putative endogenous ligand, α-endosulfine, in mesangial cells and isolated glomeruli. Further, this ligand was up-regulated by high glucose concentration. To investigate the possible role of α-endosulfine up-regulation in diabetes, we administered sulfonylureas, the exogenous ligands of SUR, to diabetic animals. Methods. In streptozotocin-induced, insulin-deficient, diabetic rats, glomerulosclerosis, albuminuria, glomerular expression of fibronectin mRNA, and glomerular filtration rate (GFR) were studied for various periods up to 36 weeks. Several rat groups received either glibenclamide or tolazamide during the entire study period. Also, glomerulosclerosis and albuminuria were determined in insulin-resistant db/db mice, at 26 weeks of treatment with tolazamide. Results. Sulfonylureas did not improve hyperglycemia or reduce glycosylated hemoglobin levels. In insulin-deficient diabetic rats, sulfonylureas significantly decreased the degree of glomerulosclerosis and completely reversed the enhanced albumin excretion. Also, glibenclamide reduced diabetes-induced glomerular overexpression of fibronectin mRNA. Because glibenclamide may improve the afferent arteriolar dilatation of diabetes, thereby reducing glomerular hyperfiltration, its effect on GFR was determined. Glibenclamide did not alter glomerular hyperfiltration or renal hypertrophy, regardless of the intensity of hyperglycemia. Finally, in insulin-resistant mice, tolazamide did not alter the extent of diabetic glomerulosclerosis or increased albuminuria. Conclusion. Long-term treatment with sulfonylureas completely prevents glomerular injury in insulin-deficient diabetes in rats. However, this protective effect is not demonstrable in an insulin-resistant model of the disease. We postulate that mesangial α-endosulfine up-regulation in the hyperglycemic milieu of insulin-deficient diabetes may retard glomerular extracellular matrix formation and mesangial expansion.

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