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

¹ Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts
² Department of Medicine, Case Western Reserve University, Cleveland, Ohio

Address correspondence and reprint requests to George L. King, Research Director, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail: george.king{at}joslin.harvard.edu

Abbreviations: 8-OHdG, 8-hydroxydeoxyguanosine; AGE, advanced glycation end product; CTGF, connective tissue growth factor; DAG, diacylglycerol; ET-1, endothelin-1; FF, filtration fraction; GFR, glomerular filtration rate; PAH, para-aminohippurate; PKC, protein kinase C; RBX, ruboxistaurin; ROS, reactive oxygen species; RPF, renal plasma flow; TGF, transforming growth factor; VEGF, vascular endothelial growth factor

Diabetes induces the activation of several protein kinase C (PKC) isoforms in the renal glomeruli. We used PKC-ß^–/– mice to examine the action of PKC-ß 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-ß^–/– mice. In wild-type mice, diabetes increased the translocation of PKC- and -ß1 to the membrane, whereas only PKC- was elevated in PKC-ß^–/– mice. Increases in urinary isoprostane and 8-hydroxydeoxyguanosine, parameters of oxidative stress, in diabetic PKC-ß^–/– mice were significantly reduced compared with diabetic wild-type mice. Diabetes increased NADPH oxidase activity and the expressions of p47^phox, Nox2, and Nox4 mRNA levels in the renal cortex and were unchanged in diabetic PKC-ß^–/– mice. Increased expression of endothelin-1 (ET-1), vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-ß, connective tissue growth factor (CTGF), and collagens IV and VI found in diabetic wild-type mice was attenuated in diabetic PKC-ß^–/– mice. Diabetic PKC-ß^–/– mice were protected from renal hypertrophy, glomerular enlargement, and hyperfiltration observed in diabetic wild-type mice and had less proteinuria. Lack of PKC-ß can protect against diabetes-induced renal dysfunction, fibrosis, and increased expressions of Nox2 and -4, ET-1, VEGF, TGF-ß, CTGF, and oxidant production.

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