Deletion of protein kinase C-epsilon signaling pathway induces glomerulosclerosis and tubulointerstitial fibrosis in vivo.
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.
Meier
Matthias
M
Department of Nephrology, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany. meier.matthias@mh-hannover.de
Menne
Jan
J
Park
Joon-Keun
JK
Holtz
Marcel
M
Gueler
Faikah
F
Kirsch
Thorsten
T
Schiffer
Mario
M
Mengel
Michael
M
Lindschau
Carsten
C
Leitges
Michael
M
Haller
Hermann
H
D000419:Albuminuria / Q000209:etiology; D000818:Animals; D003404:Creatinine / Q000652:urine; D005355:Fibrosis; D005921:Glomerulonephritis / Q000209:etiology*; D007668:Kidney / Q000473:pathology*; D007684:Kidney Tubules / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051744:Protein Kinase C-epsilon / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D053773:Transforming Growth Factor beta1; D003404:Creatinine; D051744:Protein Kinase C-epsilon; D048051:p38 Mitogen-Activated Protein Kinases