15-Epi-16-(para-fluorophenoxy)-lipoxin A4-methyl ester, a synthetic analogue of 15-epi-lipoxin A4, is protective in experimental ischemic acute renal failure

Martin O. Leonard, Kieran Hannan, Melissa J. Burne, David W.P. Lappin, Peter Doran, Patrick Coleman, Catherine Stenson, Cormac T. Taylor, Frank Daniels, Catherine Godson, Nicos A. Petasis, Hamid Rabb, Hugh R. Brady

Research output: Contribution to journalArticle

Abstract

Lipoxins are endogenous lipoxygenase-derived eicosanoids, generated during inflammatory, hypersensitivity, and vascular events, that display vasodilatory, antiinflammatory, and pro-resolution activity. Here, we evaluated the efficacy of 15-epi-16-(para-fluorophenoxy)-lipoxin A4-methyl ester (15-epi-16-(FPhO)-LXA4-Me), a stable synthetic analogue of aspirin-triggered 15-epi-lipoxin A4 in ischemic acute renal failure (ARF) in NIH Swiss mice. ARF was induced by 30-min crossclamping of renal pedicles and was associated with elevated serum creatinine, morphologic injury, polymorphonuclear leukocyte (PMN) recruitment, and increased mRNA levels for adhesion molecules (intercellular adhesion molecule-1 [ICAM-1] and vascular cell adhesion molecule-1 [VCAM-1]), chemokines (growth regulated oncogene-1 [GRO1]), and cytokines (interleukin-1β [IL-1β] and IL-6) after 24-h reperfusion. A single bolus of 15-epi-16-(FPhO)-LXA4-Me afforded striking functional (mean ± SEM creatinine in mg/dl: sham-operated, 0.77 ± 0.04; ARF + vehicle, 2.49 ± 0.19; ARF + 15-epi-16-(FPhO)-LXA4-Me, 0.75 ± 0.12; P < 0.001) and morphologic protection and reduced PMN infiltration. Treatment with 15-epi-16-(FPhO)-LXA4-Me was also associated with lower IL-1β, IL-6, and GRO1 mRNA levels, whereas ICAM-1 and VCAM-1 mRNA levels were unchanged. Compatible with these results, LXA4 blunted chemoattractant-stimulated PMN migration across HK-2 renal epithelial cell mono-layers in vitro, but it did not inhibit cytokine-induced HK-2 ICAM-1 expression or adhesiveness for PMN. Interestingly 15-epi-16-(FPhO)-LXA4-Me-treated animals also displayed increased renal mRNA levels for suppressors of cytokine signaling-1 (SOCS-1) and SOCS-2, but not CIS-1, endogenous inhibitors of cytokine-elicited Jak/Stat-signaling pathways. These results indicate that 15-epi-16-(FPhO)-LXA4-Me is protective in renal ischemia reperfusion injury in vivo, at least partially by modulating cytokine and chemokine expression and PMN recruitment, and provides a rationale for further exploration of the efficacy of LXA4 structural analogues in ischemic ARF and other renal diseases.

Original languageEnglish (US)
Pages (from-to)1657-1662
Number of pages6
JournalJournal of the American Society of Nephrology
Volume13
Issue number6
DOIs
StatePublished - Jan 1 2002
Externally publishedYes

ASJC Scopus subject areas

  • Nephrology

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    Leonard, M. O., Hannan, K., Burne, M. J., Lappin, D. W. P., Doran, P., Coleman, P., Stenson, C., Taylor, C. T., Daniels, F., Godson, C., Petasis, N. A., Rabb, H., & Brady, H. R. (2002). 15-Epi-16-(para-fluorophenoxy)-lipoxin A4-methyl ester, a synthetic analogue of 15-epi-lipoxin A4, is protective in experimental ischemic acute renal failure. Journal of the American Society of Nephrology, 13(6), 1657-1662. https://doi.org/10.1097/01.ASN.0000015795.74094.91