Lipoxin A ₄ and benzo‐lipoxin A ₄ 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.

Lipoxins Attenuate Renal Fibrosis by Inducing let-7c and Suppressing TGFβR1

“…5 Here we report that LXA 4 analog is associated with increased renal let-7c expression in vivo ( Figure 2E). …”

“…We previously demonstrated that LXA 4 attenuates collagen deposition in an animal model for renal fibrosis, and attenuates the upregulation of let-7c target COL1A2. 5 Minimal free energy calculations for let-7c pairing with 39 UTR recognition sites indicated the formation of stable hybrid structures between let-7c and COL1A1 (DG = 220.8 kcal/mol ). TGF-b1 stimulation of HK-2 cells (10 ng/ml; 24 hours) resulted in significant upregulation of COL1A1, COL1A2, and THBS1 gene expression, and transfection with let-7c miRNA mimic suppressed TGFb1-mediated upregulation of these genes ( Figure 6, B, D, and F).…”

“…[1][2][3][4] We and others recently described distinct proresolution and antifibrotic properties of lipoxins in renal fibrosis. 5,6 TGF-b1 is implicated in numerous fibrotic conditions including tubulointerstitial fibrosis and diabetic kidney disease. The development of fibrosis in this context may reflect activation of parenchymal fibroblasts, recruitment of circulating fibrocytes, and de-differentiation of epithelia and pericytes.…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Several molecules were proposed to be involved in the profibrotic switch of fibroblasts (or pericytes) during renal fibrosis, including the Wnt signaling pathway (e.g., Wnt4, LRP-6, and DKK-1) (183,184), oxidative stress and NADPH oxidase (39,88,185), integrins including aV integrin (186), Rheb/mTORC1 signaling (187) as well as lipid mediators, including prostaglandins and their receptors like EP4 (188,189), prostacyclins (190), or lipoxins (191,192).…”

Lipoxin A4 exerts protective effects against experimental acute liver failure by inhibiting the NF-κB pathway

“…Previous studies have shown that LXA4 can attenuate airway inflammation following lipopolysaccharide (LPS)-induced lung injury in mice (6), reduce systemic inflammation and improve Lipoxin A4 exerts protective effects against experimental acute liver failure by inhibiting the NF-κB pathway survival rates in a rat model of sepsis (7), suppress inflammation-induced mechanical hypersensitivity in rats (8), and inhibit pulmonary and renal fibrosis in animal models (9,10). In addition, the levels of LXA4 are decreased in patients with asthma (11).…”