The kinase Pyk2 is involved in renal fibrosis by means of mechanical stretch–induced growth factor expression in renal tubules

• DOI: 10.1038/ki.2011.403
• Publication Date: 2011-12-07T13:43:41Z
• Authors: Kazuhiro Sonomura; Mitsuhiko Okigaki; Taikou Kimura; Eiko Matsuoka; Yayoi Shiotsu; Takaomi Adachi; Hiroshi Kado; Ryo Ishida; Tetsuro Kusaba; Hiroaki Matsubara; Yasukiyo Mori
• Keywords: Male; MAP Kinase Signaling System; Smad2 Protein; Kidney; Transforming Growth Factor beta1; Mice; 03 medical and health sciences; TGF-β1; Animals; Phosphorylation; Cells, Cultured; Mice, Knockout; Pyk2; 0303 health sciences; mechanical stretch; Connective Tissue Growth Factor; CTGF; Epithelial Cells; renal fibrosis; Fibrosis; 3. Good health; Mice, Inbred C57BL; Focal Adhesion Kinase 2; Kidney Tubules; Nephrology; Models, Animal; Stress, Mechanical; Reactive Oxygen Species; Ureteral Obstruction

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.