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Deletion of Protein Kinase C- Signaling Pathway Induces Glomerulosclerosis and Tubulointerstitial Fibrosis In Vivo

Matthias Meier^*, Jan Menne^*,, Joon-Keun Park^*, Marcel Holtz^*, Faikah Gueler^*, Thorsten Kirsch^*, Mario Schiffer^*, Michael Mengel^*, Carsten Lindschau^*, Michael Leitges^* and Hermann Haller^*

^* Department of Nephrology, Hannover Medical School, and Phenos GmbH, Hannover, Germany

Address correspondence to: Dr. Matthias Meier, Department of Nephrology, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany. Phone: +49-0-511-5326319; Fax: +49-0-511-552366; E-mail: meier.matthias{at}mh-hannover.de

Received for publication July 8, 2005. Accepted for publication February 6, 2007.

Protein kinase C (PKC), a family of 12 distinct serine-threonine kinases, is an important intracellular signaling pathway involved in various cellular functions, such as proliferation, hypertrophy, apoptosis, and adhesion. PKC-, a novel PKC isoform that is activated in the diabetic kidney, has been demonstrated to have a central role in the underlying signaling infrastructure of myocardial ischemia and hypertrophy. The renal phenotype of PKC-^–/– mice was studied with regard to renal hypertrophy and fibrosis. PKC-^–/– deficient knockout mice were generated and then killed after 6, 16, and 26 wk of life. Kidney/body weight ratio did not show any significant group difference compared with appropriate wild-type controls. Urinary albumin/creatinine ratio remained normal in wild-type mice, whereas PKC-^–/– mice after 6 and 16 wk showed elevated albuminuria. Masson-Goldner staining revealed that tubulointerstitial fibrosis and mesangial expansion were significantly increased in PKC-^–/– mice. However, this profibrotic phenotype was not observed in other organs, such as liver and lung. Immunohistochemistry of the kidneys from PKC-^–/– mice showed increased renal fibronectin and collagen IV expression that was further aggravated in the streptozotocin-induced diabetic stress model. Furthermore, TGF-₁, phospho-Smad2, and phospho-p38 mitogen-activate protein kinase expression was increased in PKC-^–/– mice, suggesting a regulatory role of PKC- in TGF-₁ and its signaling pathway in the kidney. These results indicate that deletion of PKC- mediates renal fibrosis and that TGF-1 and its signaling pathway might be involved. Furthermore, these data suggest that activation of PKC- in the diabetic state may rather represent a protective response to injury than be a mediator of renal injury.

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673