Deletion of Protein Kinase C-β Isoform In Vivo Reduces Renal Hypertrophy but Not Albuminuria in the Streptozotocin-Induced Diabetic Mouse Model

Deletion of Protein Kinase C-β Isoform In Vivo Reduces Renal Hypertrophy but Not Albuminuria in the Streptozotocin-Induced Diabetic Mouse Model Matthias Meier , Joon-Keun Park , Daniel Overheu , Torsten Kirsch , Carsten Lindschau , Faikah Gueler , Michael Leitges , Jan Menne and Hermann Haller Department of Nephrology, Hannover Medical School, Hannover, Germany Address correspondence and reprint requests to Matthias Meier, MD, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany. E-mail: meier.matthias{at}mh-hannover.de Abstract The protein kinase C (PKC)-β 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-β–deficient (PKC-β −/− ) mice. We studied nondiabetic and streptozotocin-induced diabetic PKC-β −/− 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-β −/− mice. Furthermore, the high-glucose–induced expression of the profibrotic cytokine transforming growth factor (TGF)-β1 and connective tissue growth factor were significantly diminished in the diabetic PKC-β −/− mice compared with diabetic wild-type mice, suggesting a role of the PKC-β isoform in the regulation of renal hypertrophy. Notably, increased urinary albumin-to-creatinine ratio persisted in the diabetic PKC-β −/− mice. The loss of the basement membrane proteoglycan perlecan and the podocyte protein nephrin in the diabetic state was not prevented in the PKC-β −/− mice as previously demonstrated in the nonalbuminuric diabetic PKC-α −/− mice. In summary, the differential effects of PKC-β deficiency on diabetes-induced renal hypertrophy and albuminuria suggest that PKC-β contributes to high-glucose–induced TGF-β1 expression and renal fibrosis, whereas perlecan, as well as nephrin, expression and albuminuria is regulated by other signaling pathways. CTGF, connective tissue growth factor PKC, protein kinase C STZ, streptozotocin TGF, transforming growth factor VEGF, vascular endothelial growth factor WT1, Wilms’ tumor suppressor Footnotes M.M. and J.-K.P. contributed equally to this work. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18