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Diabetes 53:2101-2109, 2004
© 2004 by the American Diabetes Association, Inc.
Diminished Loss of Proteoglycans and Lack of Albuminuria in Protein Kinase C-
—Deficient Diabetic Mice
1 Phenos, Hannover, Germany
2 Department of Nephrology, Hannover Medical School, Hannover, Germany
3 Franz Vollhard Clinic, Charité, Berlin, Germany
4 Max-Planck-Institute for Experimental Endocrinology, Hannover, Germany
Activation of protein kinase C (PKC) isoforms has been implicated in the pathogenesis of diabetic nephropathy. We showed earlier that PKC-
is activated in the kidneys of hyperglycemic animals. We now used PKC-–/– mice to test the hypothesis that this PKC isoform mediates streptozotocin-induced diabetic nephropathy. We observed that renal and glomerular hypertrophy was similar in diabetic wild-type and PKC-–/– mice. However, the development of albuminuria was almost absent in the diabetic PKC-–/– mice. The hyperglycemia-induced downregulation of the negatively charged basement membrane heparan sulfate proteoglycan perlecan was completely prevented in the PKC-–/– mice, compared with controls. We then asked whether transforming growth factor-ß1 (TGF-ß1) and/or vascular endothelial growth factor (VEGF) is implicated in the PKC-–mediated changes in the basement membrane. The hyperglycemia-induced expression of VEGF165 and its receptor VEGF receptor II (flk-1) was ameliorated in PKC-–/– mice, whereas expression of TGF-ß1 was not affected by the lack of PKC-. Our findings indicate that two important features of diabetic nephropathy—glomerular hypertrophy and albuminuria—are differentially regulated. The glucose-induced albuminuria seems to be mediated by PKC- via downregulation of proteoglycans in the basement membrane and regulation of VEGF expression. Therefore, PKC- is a possible therapeutic target for the prevention of diabetic albuminuria.
Address correspondence and reprint requests to Prof. Dr. Hermann Haller, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany. E-mail: haller.hermann{at}mh-hannover.de
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