Src Kinase Mediates Renal Interstitial Fibroblast Activation and Proliferation

Abstract

Renal Interstitial fibroblast activation and proliferation is central to the development and progression of renal fibrosis after various insults, however, the signaling mechanism regulating this process is incompletely clear. In this study, we examined the role of Src, a non‐receptor tyrosine kinase in renal interstitial fibroblast activation and proliferation. Exposure of cultured renal interstitial fibroblasts (NRK‐49F) to PP1, a specific Src inhibitor, resulted in decreased expression of alpha‐Smooth muscle actin and fibronectin, two hallmarks of fibroblast activation and type 1 collagen, a key extracellular matrix protein, in a dose‐dependent manner. Silencing Src with siRNA also significantly inhibited the expression of these three proteins. Moreover, inhibition of Src kinase activity with either PP1 or siRNA, also blocked cell proliferation, decreased expression of cyclin D1, cyclin B1 and cyclin E and increased expression of p27 and p21. Finally, we showed that STAT3, AKT and ERK 1/2 were phosphorylated in cultured NRK‐49 cells and presence of PP1 or knockdown of Src with siRNA inhibited phosphorylation of all of them. Collectively, our results reveal an important role of Src in mediating activation and proliferation of renal interstitial fibroblasts and suggest that Src inhibition might be a potential therapeutic approach for attenuating renal fibrogenesis.