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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 A 4 -methyl ester (15-epi-16-(FPhO)-LXA 4 -Me), a stable synthetic analogue of aspirin-triggered 15-epi-lipoxin A 4 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 lev- with lower IL-1␤, IL-6, and GRO1 mRNA levels, whereas ICAM-1 and VCAM-1 mRNA levels were unchanged. Compatible with these results, LXA 4 blunted chemoattractant-stimulated PMN migration across HK-2 renal epithelial cell monolayers in vitro, but it did not inhibit cytokine-induced HK-2 ICAM-1 expression or adhesiveness for PMN. Interestingly 15-epi-16-(FPhO)-LXA 4 -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)-LXA 4 -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 LXA 4 structural analogues in ischemic ARF and other renal diseases.Ischemic acute renal failure (ARF) remains a formidable clinical problem for which there is no specific treatment (1). The pathophysiology of ARF is multifaceted and includes persistent intrarenal vasoconstriction, hypoxic tubule epithelial cell injury, and polymorphonuclear leukocyte (PMN)-mediated cytotoxicity upon reperfusion (1,2). Despite the impressive efficacy of agents that specifically target these processes in experimental models, none has proved effective in randomized controlled clinical trials (1). These disappointing results have shifted attention toward regimens that simultaneously target two or more of the aforementioned pathophysiologic events.Lipoxins (LX) are lipoxygenase-derived arachidonate metabolites that are generated in a variety of human and experimental inflammatory, hypersensitivity, and vascular diseases (reviewed in references 3-5). They are generated principally by transcellular routes during cell-cell interactions by biosynthetic pathways initiated through the action of two lipoxygenDr. Martin O. Leonard and Dr. Kieran Hannan contributed equally to this work.

We report the isolation and characterization of a cDNA encoding an HNF-3 family member (as HNF-3) from Atlantic salmon (Salmo salar L). The important functional domains of HNF-3 proteins that have been characterized previously are revealed by segments of high identity along the alignment of the asHNF-3 with winged helix/forkhead amino acid sequences isolated from other species. A comparison of asHNF-3 cDNA and genomic DNA indicated that there were no introns present in the asHNF-3 gene. Expression of asHNF-3 protein in adult salmon tissues was not exclusive to liver but was also present in the pancreas and intestine. An RT-PCR analysis performed on salmon development showed that asHNF3 expression is detectable before gastrulation at the mid blastula transition stage. Functional analysis of the asHNF-3 protein using a characterized HNF-3 consensus binding site demonstrated that the protein can recognize and bind to specific HNF-3 consensus sequences. We also report the identification of a novel HNF3 binding site in the promoter of the Atlantic salmon transferrin gene.

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