RT Journal Article
SR Electronic
T1 Diminished Loss of Proteoglycans and Lack of Albuminuria in Protein Kinase C-α—Deficient Diabetic Mice
JF Diabetes
JO Diabetes
FD American Diabetes Association
SP 2101
OP 2109
DO 10.2337/diabetes.53.8.2101
VO 53
IS 8
A1 Menne, Jan
A1 Park, Joon-Keun
A1 Boehne, Martin
A1 Elger, Marlies
A1 Lindschau, Carsten
A1 Kirsch, Torsten
A1 Meier, Matthias
A1 Gueler, Faikah
A1 Fiebeler, Annette
A1 Bahlmann, Ferdinand H.
A1 Leitges, Michael
A1 Haller, Hermann
YR 2004
UL http://diabetes.diabetesjournals.org/content/53/8/2101.abstract
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.