Deletion of protein kinase C-beta isoform in vivo reduces renal hypertrophy but not albuminuria in the streptozotocin-induced diabetic mouse model.
The protein kinase C (PKC)-beta isoform has been implicated to play a pivotal role in the development of diabetic kidney disease. We tested this hypothesis by inducing diabetic nephropathy in PKC-beta-deficient (PKC-beta(-/-)) mice. We studied nondiabetic and streptozotocin-induced diabetic PKC-beta(-/-) mice compared with appropriate 129/SV wild-type mice. After 8 weeks of diabetes, the high-glucose-induced renal and glomerular hypertrophy, as well as the increased expression of extracellular matrix proteins such as collagen and fibronectin, was reduced in PKC-beta(-/-) mice. Furthermore, the high-glucose-induced expression of the profibrotic cytokine transforming growth factor (TGF)-beta1 and connective tissue growth factor were significantly diminished in the diabetic PKC-beta(-/-) mice compared with diabetic wild-type mice, suggesting a role of the PKC-beta isoform in the regulation of renal hypertrophy. Notably, increased urinary albumin-to-creatinine ratio persisted in the diabetic PKC-beta(-/-) mice. The loss of the basement membrane proteoglycan perlecan and the podocyte protein nephrin in the diabetic state was not prevented in the PKC-beta(-/-) mice as previously demonstrated in the nonalbuminuric diabetic PKC-alpha(-/-) mice. In summary, the differential effects of PKC-beta deficiency on diabetes-induced renal hypertrophy and albuminuria suggest that PKC-beta contributes to high-glucose-induced TGF-beta1 expression and renal fibrosis, whereas perlecan, as well as nephrin, expression and albuminuria is regulated by other signaling pathways.
Meier
Matthias
M
Department of Nephrology, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany. meier.matthias@mh-hannover.de
Park
Joon-Keun
JK
Overheu
Daniel
D
Kirsch
Torsten
T
Lindschau
Carsten
C
Gueler
Faikah
F
Leitges
Michael
M
Menne
Jan
J
Haller
Hermann
H
D000419:Albuminuria / Q000235:genetics* / Q000517:prevention & control; D000818:Animals; D002872:Chromosome Deletion; D024141:Collagen Type IV / Q000378:metabolism; D003404:Creatinine / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental; D003928:Diabetic Nephropathies / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006984:Hypertrophy; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics; D011493:Protein Kinase C / Q000172:deficiency* / Q000235:genetics; D012313:RNA / Q000378:metabolism; D013311:Streptozocin; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism
D024141:Collagen Type IV; D005353:Fibronectins; D019812:Heparan Sulfate Proteoglycans; D008565:Membrane Proteins; D020033:Protein Isoforms; D053773:Transforming Growth Factor beta1; D042442:Vascular Endothelial Growth Factors; C113267:nephrin; C071927:perlecan; D013311:Streptozocin; D012313:RNA; D003404:Creatinine; D011493:Protein Kinase C