PT - JOURNAL ARTICLE AU - Menne, Jan AU - Park, Joon-Keun AU - Boehne, Martin AU - Elger, Marlies AU - Lindschau, Carsten AU - Kirsch, Torsten AU - Meier, Matthias AU - Gueler, Faikah AU - Fiebeler, Annette AU - Bahlmann, Ferdinand H. AU - Leitges, Michael AU - Haller, Hermann TI - Diminished Loss of Proteoglycans and Lack of Albuminuria in Protein Kinase C-α—Deficient Diabetic Mice AID - 10.2337/diabetes.53.8.2101 DP - 2004 Aug 01 TA - Diabetes PG - 2101--2109 VI - 53 IP - 8 4099 - http://diabetes.diabetesjournals.org/content/53/8/2101.short 4100 - http://diabetes.diabetesjournals.org/content/53/8/2101.full SO - Diabetes2004 Aug 01; 53 AB - Activation of protein kinase C (PKC) isoforms has been implicated in the pathogenesis of diabetic nephropathy. We showed earlier that PKC-α is activated in the kidneys of hyperglycemic animals. We now used PKC-α−/− 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-α−/− mice. However, the development of albuminuria was almost absent in the diabetic PKC-α−/− mice. The hyperglycemia-induced downregulation of the negatively charged basement membrane heparan sulfate proteoglycan perlecan was completely prevented in the PKC-α−/− mice, compared with controls. We then asked whether transforming growth factor-β1 (TGF-β1) and/or vascular endothelial growth factor (VEGF) is implicated in the PKC-α–mediated changes in the basement membrane. The hyperglycemia-induced expression of VEGF165 and its receptor VEGF receptor II (flk-1) was ameliorated in PKC-α−/− mice, whereas expression of TGF-β1 was not affected by the lack of PKC-α. 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-α via downregulation of proteoglycans in the basement membrane and regulation of VEGF expression. Therefore, PKC-α is a possible therapeutic target for the prevention of diabetic albuminuria.