title: 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.
authors.affiliation: Department of Nephrology, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany. meier.matthias@mh-hannover.de
authors.forename: Matthias
authors.initials: M
authors.lastname: Meier
authors.forename: Jan
authors.initials: J
authors.lastname: Menne
authors.forename: Joon-Keun
authors.initials: JK
authors.lastname: Park
authors.forename: Marcel
authors.initials: M
authors.lastname: Holtz
authors.forename: Faikah
authors.initials: F
authors.lastname: Gueler
authors.forename: Thorsten
authors.initials: T
authors.lastname: Kirsch
authors.forename: Mario
authors.initials: M
authors.lastname: Schiffer
authors.forename: Michael
authors.initials: M
authors.lastname: Mengel
authors.forename: Carsten
authors.initials: C
authors.lastname: Lindschau
authors.forename: Michael
authors.initials: M
authors.lastname: Leitges
authors.forename: Hermann
authors.initials: H
authors.lastname: Haller
mesh_terms: 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
chemical_list: D053773:Transforming Growth Factor beta1; D003404:Creatinine; D051744:Protein Kinase C-epsilon; D048051:p38 Mitogen-Activated Protein Kinases