Reduction of Diabetes-Induced Oxidative Stress, Fibrotic Cytokine Expression, and Renal Dysfunction in Protein Kinase Cβ–Null Mice

Abstract

Diabetes induces the activation of several protein kinase C (PKC) isoforms in the renal glomeruli. We used PKC-β−/− mice to examine the action of PKC-β isoforms in diabetes-induced oxidative stress and renal injury at 8 and 24 weeks of disease. Diabetes increased PKC activity in renal cortex of wild-type mice and was significantly reduced (<50% of wild-type) in diabetic PKC-β−/− mice. In wild-type mice, diabetes increased the translocation of PKC-α and -β1 to the membrane, whereas only PKC-α was elevated in PKC-β−/− mice. Increases in urinary isoprostane and 8-hydroxydeoxyguanosine, parameters of oxidative stress, in diabetic PKC-β−/− mice were significantly reduced compared with diabetic wild-type mice. Diabetes increased NADPH oxidase activity and the expressions of p47phox, Nox2, and Nox4 mRNA levels in the renal cortex and were unchanged in diabetic PKC-β−/− mice. Increased expression of endothelin-1 (ET-1), vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β, connective tissue growth factor (CTGF), and collagens IV and VI found in diabetic wild-type mice was attenuated in diabetic PKC-β−/− mice. Diabetic PKC-β−/− mice were protected from renal hypertrophy, glomerular enlargement, and hyperfiltration observed in diabetic wild-type mice and had less proteinuria. Lack of PKC-β can protect against diabetes-induced renal dysfunction, fibrosis, and increased expressions of Nox2 and -4, ET-1, VEGF, TGF-β, CTGF, and oxidant production.