TGFβ receptor I transactivation mediates stretch-induced Pak1 activation and CTGF upregulation in mesangial cells

Guang Chen, Xing Chen, Aravin Sukumar, Bo Gao, Jessica Curley, H. William Schnaper, Alistair J. Ingram, Joan C. Krepinsky*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3697-3712
Number of pages16
JournalJournal of cell science
Volume126
Issue number16
DOIs
StatePublished - 2013

Keywords

  • Mechanical stress
  • Pak1
  • TGFβ receptor I

ASJC Scopus subject areas

  • Cell Biology

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