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.