In:
Diabetes, American Diabetes Association, Vol. 53, No. 8 ( 2004-08-01), p. 2101-2109
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0012-1797
,
1939-327X
DOI:
10.2337/diabetes.53.8.2101
Language:
English
Publisher:
American Diabetes Association
Publication Date:
2004
detail.hit.zdb_id:
1501252-9
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