Protein kinase C [beta] inhibition attenuates the progression of experimental diabetic nephropathy in the presence of continued hypertension

In addition to hyperglycemia, hypertension and the renin-angiotensin system have been consistently implicated in the pathogenesis of diabetic nephropathy. Each of these pathogenetic factors may induce changes in cellular function by a common intracellular signaling pathway, the activation of protein kinase C (PKC) [beta]. The present study thus sought to determine the in vivo effect of PKC [beta] inhibition in experimental diabetic nephropathy in the setting of continued hyperglycemia, hypertension, and activation of the RAS. Studies were conducted in the (mRen-2)27 rat, a rodent that is transgenic for the entire mouse renin gene (Ren-2) and develops many of the structural, functional, and molecular characteristics of human diabetic nephropathy when experimental diabetes is induced with streptozotocin (STZ). Six-week-old female Ren-2 rats received an injection of STZ or vehicle and were maintained for 6 months. Within 24 h, diabetic rats were further randomized to receive treatment with the specific PKC [beta] inhibitor, LY333531, admixed in diet (10 mg * [kg.sup.-1] * [d.sup.-1]) or no treatment (n = 8/group). Diabetic rats developed albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis with a concomitant increase in transforming growth factor-[beta] (TGF-[beta]). Western blot analysis demonstrated increased PKC [beta] in diabetic animals, localized by immunofluorescence to the glomerular mesangium. In vivo inhibition of PKC [beta] with LY333531 led to a reduction in albuminuria, structural injury, and TGF-[beta] expression, despite continued hypertension and hyperglycemia.