title: Matrix-Stiffness-Regulated Inverse Expression of Krüppel-Like Factor 5 and Krüppel-Like Factor 4 in the Pathogenesis of Renal Fibrosis.
abstract: The proliferation of mouse proximal tubular epithelial cells in ex vivo culture depends on matrix stiffness. Combined analysis of the microarray and experimental data revealed that Krüppel-like factor (Klf)5 was the most up-regulated transcription factor accompanied by the down-regulation of Klf4 when cells were on stiff matrix. These changes were reversed by soft matrix via extracellular signal-regulated kinase (ERK) inactivation. Knockdown of Klf5 or forced expression of Klf4 inhibited stiff matrix-induced cell spreading and proliferation, suggesting that Klf5/Klf4 act as positive and negative regulators, respectively. Moreover, stiff matrix-activated ERK increased the protein level and nuclear translocation of mechanosensitive Yes-associated protein 1 (YAP1), which is reported to prevent Klf5 degradation. Finally, in vivo model of unilateral ureteral obstruction revealed that matrix stiffness-regulated Klf5/Klf4 is related to the pathogenesis of renal fibrosis. In the dilated tubules of obstructed kidney, ERK/YAP1/Klf5/cyclin D1 axis was up-regulated and Klf4 was down-regulated. Inhibition of collagen crosslinking by lysyl oxidase inhibitor alleviated unilateral ureteral obstruction-induced tubular dilatation and proliferation, preserved Klf4, and suppressed the ERK/YAP1/Klf5/cyclin D1 axis. This study unravels a novel mechanism how matrix stiffness regulates cellular proliferation and highlights the importance of matrix stiffness-modulated Klf5/Klf4 in the regulation of renal physiologic functions and fibrosis progression.
authors.affiliation: Institute of Basic Medical Sciences, National Cheng-Kung University Medical College, Tainan, Taiwan.
authors.forename: Wan-Chun
authors.initials: WC
authors.lastname: Chen
authors.affiliation: Department of Physiology, National Cheng-Kung University Medical College, Tainan, Taiwan. Electronic address: sophialin0113@hotmail.com.
authors.forename: Hsi-Hui
authors.initials: HH
authors.lastname: Lin
authors.affiliation: Institute of Basic Medical Sciences, National Cheng-Kung University Medical College, Tainan, Taiwan; Department of Physiology, National Cheng-Kung University Medical College, Tainan, Taiwan. Electronic address: mjtang1@mail.ncku.edu.tw.
authors.forename: Ming-Jer
authors.initials: MJ
authors.lastname: Tang
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D015854:Up-Regulation
chemical_list: C000715468:Klf4 protein, mouse; C118391:Klf5 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D048049:Extracellular Signal-Regulated MAP Kinases