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

J Pathol. 2012 Dec;228(4):506-19. doi: 10.1002/path.4050. Epub 2012 Nov 6.


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.

Keywords: AKT; ChemR23; ERK; PDGF; UUO; fibroblast; proliferation; renal fibrosis; resolvin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Becaplermin
  • Cell Proliferation / drug effects
  • Docosahexaenoic Acids / pharmacology*
  • Eicosapentaenoic Acid / analogs & derivatives*
  • Eicosapentaenoic Acid / pharmacology
  • Fibroblasts / drug effects*
  • Fibroblasts / pathology*
  • Fibrosis / drug therapy
  • Fibrosis / pathology
  • Kidney / drug effects
  • Kidney / pathology
  • Macrophages / drug effects
  • Macrophages / pathology
  • Male
  • Mice, Inbred C57BL
  • Primary Cell Culture
  • Proto-Oncogene Proteins c-sis / pharmacology
  • Ureteral Obstruction / drug therapy*
  • Ureteral Obstruction / pathology*


  • Proto-Oncogene Proteins c-sis
  • resolvin D1
  • Becaplermin
  • Docosahexaenoic Acids
  • Eicosapentaenoic Acid
  • 5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid