Diminished Loss of Proteoglycans and Lack of Albuminuria in Protein Kinase C-α—Deficient Diabetic Mice
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.
- AT, tuft area
- ĀT, average tuft area
- GBM, glomerular basement membrane
- PFA, paraformaldehyde
- PKC, protein kinase C
- TGF, transforming growth factor
- VEGF, vacular endothelial growth factor
- VEGFR, VEGF receptor
- VT, tuft volume
- WT, wild type
Footnotes
J.M. and J.-K.P. contributed equally to this work.
H.H. is a member of the advisory panel of Aventis, Bayer, MSD, Sankyo, Novartis, and Lilly, manufacturers of pharmaceuticals related to the treatment of diabetes. He has received honoraria for speaking engagements from AstraZeneca, Aventis, Bayer, Baxter, Berlin-Chemie, Boehringer Ingelheim, MSD, Novartis, Roche, Sanofi, and Sankyo. He is also a paid consultant for Amgen and Sankyo. Bayer, Berlin-Chemie, MSD, Sanofi, and Sankyo provide funds to H.H.’s laboratory to conduct studies on a new drug to treat diabetic complications.
- Accepted April 30, 2004.
- Received November 24, 2003.
- DIABETES