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