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

Hubchak SC, Sparks EE, Hayashida T, Schnaper HW. Rac1 promotes TGF-stimulated mesangial cell type I collagen expression through a PI3K/Akt-dependent mechanism. Am J Physiol Renal Physiol 297: F1316 –F1323, 2009. First published September 2, 2009; doi:10.1152/ajprenal.00345.2009.—Transforming growth factor (TGF)is a central mediator in the progression of glomerulosclerosis, leading to accumulation of aberrant extracellular matrix proteins and inappropriate expression of smooth muscle -actin in the kidney. Previously, we reported that disrupting the cytoskeleton diminished TGF-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. TGF1 activated both RhoA and Rac1 within 5 min of treatment, and this activation was dependent on the kinase activity of the type I TGFreceptor. TGF1-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 TGF1-stimulated COL1A2 promoter activity and Rac1 activation. It also partially blocked active Rac1-stimulated collagen promoter activity, suggesting that PI3K activity contributes to both TGFactivation of Rac1 and signal propagation downstream of Rac1. Thus, while both Rac1 and RhoA are rapidly activated in response to TGF1 in human mesangial cells, only Rac1 activation enhances events that contribute to mesangial cell collagen expression, through a positive feedback loop involving PI3K.