Deletion of protein kinase C-epsilon signaling pathway induces glomerulosclerosis and tubulointerstitial fibrosis in vivo.

ABSTRACT

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-epsilon, 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-epsilon(-/-) mice was studied with regard to renal hypertrophy and fibrosis. PKC-epsilon(-/-) 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-epsilon(-/-) mice after 6 and 16 wk showed elevated albuminuria. Masson-Goldner staining revealed that tubulointerstitial fibrosis and mesangial expansion were significantly increased in PKC-epsilon(-/-) mice. However, this profibrotic phenotype was not observed in other organs, such as liver and lung. Immunohistochemistry of the kidneys from PKC-epsilon(-/-) mice showed increased renal fibronectin and collagen IV expression that was further aggravated in the streptozotocin-induced diabetic stress model. Furthermore, TGF-beta(1), phospho-Smad2, and phospho-p38 mitogen-activate protein kinase expression was increased in PKC-epsilon(-/-) mice, suggesting a regulatory role of PKC-epsilon in TGF-beta(1) and its signaling pathway in the kidney. These results indicate that deletion of PKC-epsilon mediates renal fibrosis and that TGF-beta1 and its signaling pathway might be involved. Furthermore, these data suggest that activation of PKC-epsilon in the diabetic state may rather represent a protective response to injury than be a mediator of renal injury.