Fyn, a target for treatment of renal fibrosis

Abstract

Renal tubulointerstitial fibrosis is a leading cause of chronic kidney disease. The hallmark of tubulointerstitial fibrosis is accumulation of myofibroblasts and extracellular matrix (ECM) proteins, driven mainly by transforming growth factor- β (TGF-β) /Smad signaling. It is generally accepted that TGF-β activates downstream Smad signaling to regulate fibrosis-related gene expression. However, emerging evidence suggests that non-Smad signaling pathways are also involved in TGF- β –mediated fibrosis. The Src family kinases are a group of non-receptor tyrosine kinases that regulate a variety of cell functions including migration, invasion, and growth. Src kinases are activated in response to TGF-β stimulation and promote pulmonary fibrosis. Moreover, Src contributes to TGF-β –induced plasminogen activator inhibitor -1 via its interaction with epidermal growth factor receptor expression in vascular smooth muscle cells. Thus, Src family kinases might also be involved in TGF- β –mediated, non-Smad signaling. The signal transducer and activator of transcription 3 (STAT3) mediates multiple cellular functions including cell survival, proliferation, and fibrosis. In addition, it induces expression of multiple genes, including TGF- β and elevated STAT3 is related with progression of renal fibrosis. Fyn, a member of the Src family of kinases, has diverse biological functions including regulation of mitogenic signaling and proliferation, integrin-mediated interaction, and adhesion-mediated signaling. We recently found that Fyn was activated in animals with unilateral ureteral obstruction-induced renal fibrosis, and that Fyn inhibition attenuated fibrosis by down-regulating STAT-3. In this talk, I will present our study that the role of Fyn in renal fibrosis.