title: TGFβ receptor I transactivation mediates stretch-induced Pak1 activation and CTGF upregulation in mesangial cells.
abstract: Increased intraglomerular pressure is an important pathogenic determinant of kidney fibrosis in the progression of chronic kidney disease, and can be modeled by exposing glomerular mesangial cells (MC) to mechanical stretch. MC produce extracellular matrix and profibrotic cytokines, including connective tissue growth factor (CTGF) when stretched. We show that p21-activated kinase 1 (Pak1) is activated by stretch in MC in culture and in vivo in a process marked by elevated intraglomerular pressures. Its activation is essential for CTGF upregulation. Rac1 is an upstream regulator of Pak1 activation. Stretch induces transactivation of the type I transforming growth factor β1 receptor (TβRI) independently of ligand binding. TβRI transactivation is required not only for Rac1/Pak1 activation, but also for activation of the canonical TGFβ signaling intermediate Smad3. We show that Smad3 activation is an essential requirement for CTGF upregulation in MC under mechanical stress. Pak1 regulates Smad3 C-terminal phosphorylation and transcriptional activation. However, a second signaling pathway, that of RhoA/Rho-kinase and downstream Erk activation, is also required for stretch-induced CTGF upregulation in MC. Importantly, this is also regulated by Pak1. Thus, Pak1 serves as a novel central mediator in the stretch-induced upregulation of CTGF in MC.
authors.affiliation: Division of Nephrology, St. Joseph's Hospital, McMaster University, Hamilton, ON L8N 4A6, Canada.
authors.forename: Guang
authors.initials: G
authors.lastname: Chen
authors.forename: Xing
authors.initials: X
authors.lastname: Chen
authors.forename: Aravin
authors.initials: A
authors.lastname: Sukumar
authors.forename: Bo
authors.initials: B
authors.lastname: Gao
authors.forename: Jessica
authors.initials: J
authors.lastname: Curley
authors.forename: H William
authors.initials: HW
authors.lastname: Schnaper
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Ingram
authors.forename: Joan C
authors.initials: JC
authors.lastname: Krepinsky
mesh_terms: D000818:Animals; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050527:Mesangial Cells / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D051436:Renal Insufficiency, Chronic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D015533:Transcriptional Activation; D015854:Up-Regulation; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C526317:CCN2 protein, human; D018125:Receptors, Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; C515903:PAK1 protein, human; D054462:p21-Activated Kinases
keywords: Mechanical stress; Pak1; TGFβ receptor I