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Free keywords:
Albuminuria/urine; Animals; Base Sequence; Blood Glucose/metabolism; Body Weight; DNA Primers; Diabetes Mellitus, Experimental/blood/genetics/urine; Diabetic Nephropathies/genetics/pathology/urine; Hyperglycemia/genetics/physiopathology; Kidney/anatomy and histology/pathology/ultrastructure; Kidney Glomerulus/anatomy and histology; Mice; Mice, Inbred Strains; Mice, Knockout; Organ Size; Protein Kinase C/deficiency/genetics; Proteoglycans/metabolism; Research Support, Non-U.S. Gov't; Reverse Transcriptase Polymerase Chain Reaction; Vascular Endothelial Growth Factor A/blood/genetics; Vascular Endothelial Growth Factor Receptor-2/genetics
Abstract:
Activation of protein kinase C (PKC) isoforms has been implicated in the pathogenesis of diabetic nephropathy. We showed earlier that PKC-alpha is activated in the kidneys of hyperglycemic animals. We now used PKC-alpha(-/-) 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-alpha(-/-) mice. However, the development of albuminuria was almost absent in the diabetic PKC-alpha(-/-) mice. The hyperglycemia-induced downregulation of the negatively charged basement membrane heparan sulfate proteoglycan perlecan was completely prevented in the PKC-alpha(-/-) mice, compared with controls. We then asked whether transforming growth factor-beta1 (TGF-beta1) and/or vascular endothelial growth factor (VEGF) is implicated in the PKC-alpha-mediated changes in the basement membrane. The hyperglycemia-induced expression of VEGF165 and its receptor VEGF receptor II (flk-1) was ameliorated in PKC-alpha(-/-) mice, whereas expression of TGF-beta1 was not affected by the lack of PKC-alpha. 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-alpha via downregulation of proteoglycans in the basement membrane and regulation of VEGF expression. Therefore, PKC-alpha is a possible therapeutic target for the prevention of diabetic albuminuria.
