Resolvins E1 and D1 inhibit interstitial fibrosis in the obstructed kidney via inhibition of local fibroblast proliferation

Abstract

Resolvin E1 (RvE1) is a naturally occurring lipid-derived mediator generated during the resolution of inflammation. The anti-inflammatory effects of RvE1 have been demonstrated in a variety of disease settings; however, it is not known whether RvE1 may also exert direct anti-fibrotic effects. We examined the potential anti-fibrotic actions of RvE1 in the mouse obstructed kidney-a model in which tissue fibrosis is driven by unilateral ureteric obstruction (UUO), an irreversible, non-immune insult. Administration of RvE1 (300 ng/day) to mice significantly reduced accumulation of α-smooth muscle actin (SMA)(+) myofibroblasts and the deposition of collagen IV on day 6 after UUO. This protective effect was associated with a marked reduction of myofibroblast proliferation on days 2, 4 and 6 after UUO. RvE1 treatment also inhibited production of the major fibroblast mitogen, platelet-derived growth factor-BB (PDGF-BB), in the obstructed kidney. Acute resolvin treatment over days 2-4 after UUO also had a profound inhibitory effect upon myofibroblast proliferation without affecting the PDGF expression, suggesting a direct effect upon fibroblast proliferation. In vitro studies established that RvE1 can directly inhibit PDGF-BB-induced proliferation in primary mouse fibroblasts. RvE1 induced transient, but not sustained, activation of the pro-proliferative ERK and AKT signalling pathways. Of note, RvE1 inhibited the sustained activation of ERK and AKT pathways seen in response to PDGF stimulation, thereby preventing up-regulation of molecules required for progression through the cell cycle (c-Myc, cyclin D) and down-regulation of inhibitors of cell cycle progression (p21, cip1). Finally, siRNA-based knock-down studies showed that the RvE1 receptor, ChemR23, is required for the anti-proliferative actions of RvE1 in cultured fibroblasts. In conclusion, this study demonstrates that RvE1 can inhibit fibroblast proliferation in vivo and in vitro, identifying RvE1 as a novel anti-fibrotic therapy.