title: Lipoxin A₄ and benzo-lipoxin A₄ attenuate experimental renal fibrosis.
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.
authors.affiliation: University College Dublin, Diabetes Research Centre, UCD Conway Institute, School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland.
authors.forename: Emma
authors.initials: E
authors.lastname: Börgeson
authors.forename: Neil G
authors.initials: NG
authors.lastname: Docherty
authors.forename: Madeline
authors.initials: M
authors.lastname: Murphy
authors.forename: Karen
authors.initials: K
authors.lastname: Rodgers
authors.forename: Aidan
authors.initials: A
authors.lastname: Ryan
authors.forename: Tim P
authors.initials: TP
authors.lastname: O'Sullivan
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Guiry
authors.forename: Roel
authors.initials: R
authors.lastname: Goldschmeding
authors.forename: Debra F
authors.initials: DF
authors.lastname: Higgins
authors.forename: Catherine
authors.initials: C
authors.lastname: Godson
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis / Q000188:drug therapy / Q000517:prevention & control; D005786:Gene Expression Regulation; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D007674:Kidney Diseases / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D008026:Ligation; D044045:Lipoxins / Q000737:chemistry / Q000627:therapeutic use*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D044045:Lipoxins; D053773:Transforming Growth Factor beta1; C040527:lipoxin A4; D003094:Collagen; C562252:benzo-lipoxin A4