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Deletion of Protein Kinase C-ß Isoform In Vivo Reduces Renal Hypertrophy but Not Albuminuria in the Streptozotocin-Induced Diabetic Mouse Model

Department of Nephrology, Hannover Medical School, Hannover, Germany

Address correspondence and reprint requests to Matthias Meier, MD, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany. E-mail: meier.matthias{at}mh-hannover.de

Abbreviations: CTGF, connective tissue growth factor; PKC, protein kinase C; STZ, streptozotocin; TGF, transforming growth factor; VEGF, vascular endothelial growth factor; WT1, Wilms’ tumor suppressor

The protein kinase C (PKC)-ß isoform has been implicated to play a pivotal role in the development of diabetic kidney disease. We tested this hypothesis by inducing diabetic nephropathy in PKC-ß–deficient (PKC-ß^–/–) mice. We studied nondiabetic and streptozotocin-induced diabetic PKC-ß^–/– mice compared with appropriate 129/SV wild-type mice. After 8 weeks of diabetes, the high-glucose–induced renal and glomerular hypertrophy, as well as the increased expression of extracellular matrix proteins such as collagen and fibronectin, was reduced in PKC-ß^–/– mice. Furthermore, the high-glucose–induced expression of the profibrotic cytokine transforming growth factor (TGF)-ß1 and connective tissue growth factor were significantly diminished in the diabetic PKC-ß^–/– mice compared with diabetic wild-type mice, suggesting a role of the PKC-ß isoform in the regulation of renal hypertrophy. Notably, increased urinary albumin-to-creatinine ratio persisted in the diabetic PKC-ß^–/– mice. The loss of the basement membrane proteoglycan perlecan and the podocyte protein nephrin in the diabetic state was not prevented in the PKC-ß^–/– mice as previously demonstrated in the nonalbuminuric diabetic PKC-^–/– mice. In summary, the differential effects of PKC-ß deficiency on diabetes-induced renal hypertrophy and albuminuria suggest that PKC-ß contributes to high-glucose–induced TGF-ß1 expression and renal fibrosis, whereas perlecan, as well as nephrin, expression and albuminuria is regulated by other signaling pathways.

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