Figure 11.
A model for Rac1 involvement in TGF-β1–driven renal fibrosis. Rac1 is rapidly activated in response to TGF-β1 stimulation and likely facilitates the assembly of NOX1 and NOX2 signaling complexes in the renal cellular plasma membrane. NADP(H)-mediated generation of free radicals in response to TGF-β1 induces ATM and p53 phosphorylation as well as EGFR and c-Src activation. The resulting accumulation of p-p53Ser15 and pSMAD3 transcriptional complexes on the promoter of TGF-β1 target genes mediates fibrotic reprogramming and PAI-1–dependent cell cycle arrest. Rac1b and NOX subunit expression is dramatically increased in UUO-driven renal injury. Chemical blockade of Rac attenuated progressive renal fibrosis and Rac1b, NOX, YAP/TAZ, p53, and EGFR activation in the kidney. Therefore, Rac1 is a new non-SMAD control element of the TGF-β1 pathway and a novel therapeutic target against CKD.