Differential expression of protein kinase C isoforms in streptozotocin-induced diabetic rats

Background. The cellular effects of hyperglycemia are mediated by protein k inase C (PKC). However, PE;C consists of several distinct isoforms, and the ir contribution to the pathogenesis of diabetic complications in different organs is not clear. We investigated the expression and translocation of PK C isoforms alpha, beta I, beta II, delta, epsilon, and zeta in kidney, hear t, and aorta from diabetic rats. Methods. Hyperglycemia was induced with streptozotocin (70 mg/kg) in the ra t. After four weeks, PKC isoform expression was assessed by Western blot af ter tissue fractionation and by immunohistochemistry. Results. Streptozotocin increased blood glucose from 117.0 +/- 3.6 to 510.0 +/- 19.4 mg/dl (N = 8, P < 0.01) and induced albuminuria. PKC isoforms alp ha, beta I, beta II, delta, epsilon, and zeta were all detected in control animals. Western blot showed increased PKC a expression in kidney and heart (160% and 170%, respectively). PKC beta I, beta III and delta expression w as not influenced by hyperglycemia. PE;C 5 was decreased in diabetic animal s in both tissues by 60%. The membrane association of PKC alpha and PKC eps ilon was increased; however, the relative amount of PKC in the particulate fraction was not influenced by hyperglycemia. Immunohistochemistry revealed a marked increase in PKC alpha immunoreactivity in renal glomeruli and int erstitial capillaries, cardiac capillaries, and skeletal muscle, as well as in the endothelial cells of larger arteries. PKC beta showed a small decre ase in the glomeruli. PKC epsilon was increased in renal tubules in diabeti c rats but was decreased in the myocardium. PKC zeta was expressed in both myocardial and glomerular cells but was decreased during hyperglycemia. Our results demonstrate that PKC isoforms are differentially regulated in kidn ey and heart in diabetes. High glucose increases PKC alpha expression, wher eas PKC zeta is down-regulated. The finding that PKC alpha is mostly increa sed in endothelial cells supports a role for PKC alpha in functional endoth elial disturbances observed in diabetes.