Gene expression for endothelins and their receptors in glomeruli of diabetic rats.

The present study was designed to assess levels of messenger RNA encoding for endothelin-1, endothelin-3, and endothelin receptors A and B in glomeruli of rats with streptozotocin-induced diabetes at 4, 12, and 24 weeks of age. In addition, streptozotocin-induced rats with diabetes were either treated with 8 to 14 units neutral protamine Hagedorn insulin daily to maintain moderate hyperglycemia (approximately 200 mg/dl) or left untreated to produce severe hyperglycemia (more than 400 mg/dl) during the 4-week study period. The messenger RNA levels for endothelin-1 in glomeruli of diabetic rats increased with the progression of diabetic nephropathy (4 weeks, 2.5 times control level, p < 0.01; 12 weeks, 3.8 times, p < 0.01; and 24 weeks, 5.3 times, p < 0.001. In contrast, messenger RNA levels for endothelin receptors A and B were not altered in glomeruli from diabetic and control rats throughout the experimental period. Messenger RNA for endothelin-3 in glomeruli from diabetic and control rats was not detected until 24 weeks of age. Insulin treatment partially ameliorated the increase in messenger RNA for endothelin-1 in the glomeruli of diabetic rats (0.3 times compared with diabetic rats without insulin treatment, p < 0.01), whereas insulin treatment did not affect messenger RNA for endothelin receptors A and B in diabetic glomeruli. These findings indicate that increased endothelin-1 messenger RNA in glomeruli may be a manifestation of diabetic nephropathy, and hyperglycemia or insulin-deficiency may play a role in abnormal endothelin-1 gene regulation.