Lipoxin A₄ and benzo-lipoxin A₄ attenuate experimental renal fibrosis.

Unresolved inflammation underlies the development of fibrosis and organ failure. Here, we investigate the potential of the proresolving eicosanoid lipoxinA(4) (LXA(4)) and its synthetic analog benzo-LXA(4) to prophylactically modulate fibrotic and inflammatory responses in a model of early renal fibrosis, unilateral ureteric obstruction (UUO). Male Wistar rats (Animalia, Chordata, Rattus norvegicus) were injected intravenously with vehicle (0.1% ethanol), LXA(4) (45 mu g/250-g rat), or benzo-LXA(4) (15 mu g/250-g rat) 15 min prior to surgery and sacrificed 3 d postligation. Renal gene and protein expression, collagen deposition, macrophage infiltration, and apoptosis were analyzed using manipulated kidneys from sham operations as control. Lipoxins (LXs) attenuated collagen deposition and renal apoptosis (P<0.05) and shifted the inflammatory milieu toward resolution, inhibiting TNF-alpha and IFN-gamma expression, while stimulating proresolving IL-10. LXs attenuated UUO-induced activation of MAP kinases, Akt, and Smads (P<0.05) in injured kidneys. We explored whether the underlying mechanism reflected LX-induced modulation of fibroblast activation. Using cultured rat renal NRK-49F fibroblasts, we report that LXA(4) (1 nM) inhibits TGF-beta 1 (10 ng/ml)-induced activation of Smad2 and MAP-kinases (P<0.05), and furthermore, LXA(4) reduced TGF-beta 1-stimulated PAI-1 luciferase activation (P<0.05) relative to vehicle-stimulated cells. We propose that LXs may represent a potentially useful and novel therapeutic strategy for consideration in the context of renal fibrosis.-Borgeson, E., Docherty, N. G., Murphy, M., Rodgers, K., Ryan, A., O'Sullivan, T. P., Guiry, P. J., Goldschmeding, R., Higgins, D. F., Godson, C. Lipoxin A(4) and benzo-lipoxin A(4) attenuate experimental renal fibrosis. FASEB J. 25, 2967-2979 (2011). www.fasebj.org