title: The kinase Pyk2 is involved in renal fibrosis by means of mechanical stretch-induced growth factor expression in renal tubules.
abstract: Unilateral ureteral obstruction is a well-established experimental model of progressive renal fibrosis. We tested whether mechanical stretch and subsequent renal tubular distension might lead to renal fibrosis by first studying renal tubular epithelial cells in culture. We found that mechanical stretch induced reactive oxygen species that in turn activated the cytoplasmic proline-rich tyrosine kinase-2 (Pyk2). This kinase is abundantly expressed in tubular epithelial cells where it is activated by several stimuli. Using mice with deletion of Pyk2 we found that the expression of transforming growth factor-β1 induced by mechanical stretch in renal tubular epithelial cells was significantly reduced. The expression of connective tissue growth factor was also reduced in the Pyk2(-/-) mice. We also found that expression of connective tissue growth factor was independent of transforming growth factor-β1, but dependent on the Rho-associated coiled-coil forming protein kinase pathway. Thus, Pyk2 may be an important initiating factor in renal fibrosis and might be a new therapeutic target for ameliorating renal fibrosis.
authors.affiliation: Department of Cardiology and Nephrology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Sonomura
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Okigaki
authors.forename: Taikou
authors.initials: T
authors.lastname: Kimura
authors.forename: Eiko
authors.initials: E
authors.lastname: Matsuoka
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Shiotsu
authors.forename: Takaomi
authors.initials: T
authors.lastname: Adachi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kado
authors.forename: Ryo
authors.initials: R
authors.lastname: Ishida
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Kusaba
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsubara
authors.forename: Yasukiyo
authors.initials: Y
authors.lastname: Mori
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D051418:Focal Adhesion Kinase 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism* / Q000473:pathology*; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism; D013314:Stress, Mechanical; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014517:Ureteral Obstruction / Q000150:complications
chemical_list: D017382:Reactive Oxygen Species; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D051418:Focal Adhesion Kinase 2; C496053:Ptk2b protein, mouse