EXPRESSION OF GROWTH-RELATED PROTOONCOGENES DURING DIABETIC RENAL HYPERTROPHY

Experimental type 1 diabetes mellitus is characterized by an early increase in kidney weight and glomerular volume, but changes in gene expression accompanying diabetic renal growth have not been elucidated. The early response genes, c-fos, c-jun, and c-myc encode proteins that regulate gene transcription, thus influencing the cellular responses to a stimulus. Accordingly, we studied c-fos, c-jun, and c-myc expression in glomeruli during the rapid phase of glomerular hypertrophy that follows the onset of hyperglycemia in diabetic rats. Total RNA was extracted by the method of Chomczynski from isolated glomeruli of streptozotocin (60 mg/kg i.v.) induced diabetic rats 24, 48, and 96 hours, and 1 week after the onset of hyperglycemia (blood glucose >15 mmol/liter). A second group of rats, studied after streptozotocin administration, received twice daily insulin to maintain normoglycemia. A group of age-matched normal rats served as the control group. Northern blot analysis was performed with cDNA probes for c-fos, c-jun, and c-myc, and GAPDH. mRNA levels for c-fos increased fourfold 24 hours after the onset of hyperglycemia, but returned to baseline by 48 hours. mRNA levels for c-jun increased threefold 24 hours after the onset of hyperglycemia, in diabetic glomeruli, and the increase was sustained for one week. Intensive insulin treatment normalized blood glucose revels and abrogated the increases in c-fos and c-jun expression. There was no discernable increase in c-myc mRNA levels in the diabetic glomeruli. We conclude that the early phase of glomerular growth following the onset of hyperglycemia in diabetic rats is accompanied by increased c-fos and c-jun expression.