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ID: 270921.0, MPI für biophysikalische Chemie / Abteilungsunabhängige Arbeitsgruppen
Diminished loss of proteoglycans and lack of albuminuria in protein kinase C-alpha-deficient diabetic mice.
Authors:Menne, J.; Park, J. K.; Boehne, M.; Elger, M.; Lindschau, C.; Kirsch, T.; Meier, M.; Gueler, F.; Fiebeler, A.; Bahlmann, F. H.; Leitges, M.; Haller, H.
Date of Publication (YYYY-MM-DD):2004-08
Title of Journal:Diabetes
Issue / Number:8
Start Page:2101
End Page:2109
Review Status:Peer-review
Audience:Experts Only
Abstract / Description: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.
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
External Publication Status:published
Document Type:Article
Communicated by:N. N.
Affiliations:MPI für biophysikalische Chemie/AG Leitges
MPI für biophysikalische Chemie/Abt. Eichele
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