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FASEB J. 2011 Sep;25(9):2967-79. doi: 10.1096/fj.11-185017. Epub 2011 May 31.

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

Author information

1
University College Dublin, Diabetes Research Centre, UCD Conway Institute, School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland.

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-β1 (10 ng/ml)-induced activation of Smad2 and MAP-kinases (P<0.05), and furthermore, LXA₄ reduced TGF-β1-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.

PMID:
21628447
DOI:
10.1096/fj.11-185017
[Indexed for MEDLINE]

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