Rac1 promotes TGF-β-stimulated mesangial cell type I collagen expression through a PI3K/Akt-dependent mechanism

Susan C. Hubchak, Erin E. Sparks, Tomoko Hayashida, H. William Schnaper

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

Transforming growth factor (TGF)-β is a central mediator in the progression of glomerulosclerosis, leading to accumulation of aberrant extracellular matrix proteins and inappropriate expression of smooth muscle α-actin in the kidney. Previously, we reported that disrupting the cytoskeleton diminished TGF-β-stimulated type I collagen accumulation in human mesangial cells. As cytoskeletal signaling molecules, including the Rho-family GTPases, have been implicated in fibrogenesis, we sought to determine the respective roles of RhoA and Rac1 in HMC collagen I expression. TGF-β1 activated both RhoA and Rac1 within 5 min of treatment, and this activation was dependent on the kinase activity of the type I TGF-β receptor. TGF-β1-stimulated induction of type I collagen mRNA expression and promoter activity was diminished by inhibiting Rac1 activity and was increased by a constitutively active Rac1 mutant, whereas inhibiting RhoA activity had no such effect. Rac1 activation required phosphatidylinositol-3-kinase (PI3K) activity. Furthermore, the PI3K antagonist, LY294002, reduced TGF-β1-stimulated COL1A2 promoter activity and Rac1 activation. It also partially blocked active Rac1-stimulated collagen promoter activity, suggesting that PI3K activity contributes to both TGF-β activation of Rac1 and signal propagation downstream of Rac1. Thus, while both Rac1 and RhoA are rapidly activated in response to TGF-β1 in human mesangial cells, only Rac1 activation enhances events that contribute to mesangial cell collagen expression, through a positive feedback loop involving PI3K.

Original languageEnglish (US)
Pages (from-to)F1316-F1323
JournalAmerican Journal of Physiology - Renal Physiology
Volume297
Issue number5
DOIs
StatePublished - Nov 2009

Keywords

  • Fibrosis
  • Kidney
  • Rho-GTPase

ASJC Scopus subject areas

  • Physiology
  • Urology

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