ABSTRACT
Unresolved inflammation underlies the development of fibrosis and organ failure. Here, we investigate the potential of the proresolving eicosanoid lipoxinA4 (LXA4) and its synthetic analog benzo-LXA4 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), LXA4 (45 µg/250-g rat), or benzo-LXA4 (15 µg/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-α and IFN-γ 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 LXA4 (1 nM) inhibits TGF-ß1 (10 ng/ml)-induced activation of Smad2 and MAP-kinases (P<0.05), and furthermore, LXA4 reduced TGF-ß1-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.
