EXPRESSION OF GROWTH-RELATED PROTOONCOGENES DURING DIABETIC RENAL HYPERTROPHY

Experimental type 1 diabetes mellitus is characterized by an early inc rease in kidney weight and glomerular volume, but changes in gene expr ession accompanying diabetic renal growth have not been elucidated. Th e early response genes, c-fos, c-jun, and c-myc encode proteins that r egulate gene transcription, thus influencing the cellular responses to a stimulus. Accordingly, we studied c-fos, c-jun, and c-myc expressio n in glomeruli during the rapid phase of glomerular hypertrophy that f ollows the onset of hyperglycemia in diabetic rats. Total RNA was extr acted by the method of Chomczynski from isolated glomeruli of streptoz otocin (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 a ge-matched normal rats served as the control group. Northern blot anal ysis was performed with cDNA probes for c-fos, c-jun, and c-myc, and G APDH. mRNA levels for c-fos increased fourfold 24 hours after the onse t of hyperglycemia, but returned to baseline by 48 hours. mRNA levels for c-jun increased threefold 24 hours after the onset of hyperglycemi a, in diabetic glomeruli, and the increase was sustained for one week. Intensive insulin treatment normalized blood glucose revels and abrog ated the increases in c-fos and c-jun expression. There was no discern able increase in c-myc mRNA levels in the diabetic glomeruli. We concl ude that the early phase of glomerular growth following the onset of h yperglycemia in diabetic rats is accompanied by increased c-fos and c- jun expression.