Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Emerging roles for eicosanoids in renal diseases Niels O.S. Ca ˆmara, Joilson O. Martins, Richardt G. Landgraf and Sonia Jancar Introduction Cellular responses are followed by rapid remodeling of membrane phospholipids by activated lipases with con- comitant generation of biologically active lipids that can act as mediators of intracellular or extracellular events. Activation of phospholipases is a critical step in the synthesis of these mediators because they cleave mem- brane phospholipids generating arachidonic acid (AA), an essential fatty acid with 20 carbon atoms and 4 double bonds, which can be bioconverted into eicosanoids via a variety of metabolic pathways. The best known pathways are the cyclooxygenase (COX) which converts AA into prostanoids, the 5-lipoxygenase (5-LO) which converts AA into leukotrienes and the cytochrome p450 (CYP-450) pathway which gives rise to both epoxyeicosatrienoic and 20-hydroxyeicosatetraenoic acid. Prostanoids are generated via COX or prostaglandin H (PGH) synthase which incorporates molecular oxygen into AA to form PGH 2 , which is further metabolized by prostanoid synthases, PGES, PGIS, PGDS, PGFS, and TXS, responsible for PGE 2 , PGI 2 , PGD, PGF 2a , and TXA 2 biosynthesis, respectively. Three PGES have been identified: microsomal PGES1 and 2 and cytosolic PGES. The PGES1 is induced by inflammatory cytokines and mediators, whereas mPGES2 and cPGES are constitu- tively expressed. Two isoforms of COX are well described, with COX-1 being the constitutive enzyme originally found in bovine prostate. Ferreira et al. in 1971 suggested that the mech- anism of anti-inflammatory effect of the nonsteroid anti- inflammatory drugs involved inhibition of prostaglandin synthesis [1]. Following the discovery in 1990 of a COX induced by inflammatory stimuli (COX-2), a series of compounds were developed which were more selective for this enzyme. Approximately 60% of the polypeptide sequences of COX-1 and COX-2 are similar, although their regulation is quite different [2]. However, it was later found that COX-2 is expressed constitutively in certain tissues (vascular endothelium, respiratory epi- thelium, central nervous system) and is thus responsible for prostanoid synthesis for homeostatic functions. A third isoform (COX-3) has been described in rodents with an as yet unknown function. In humans, there are physiological processes in which each COX isozyme is uniquely involved (e.g. platelet aggrega- tion for COX-1; ovulation, blastocyst implantation, inflam- mation resolution, perinatal kidney development; and ulcer healing for COX-2) and others in which both Department of Immunology, Institute of Biomedical Sciences, University of Sa ˜o Paulo, Sa ˜ o Paulo, SP, Brazil Correspondence to Sonia Jancar, PhD, Department of Immunology, Institute of Biomedical Sciences, University of Sa ˜ o Paulo, Av. Prof. Lineu Prestes 1730, 05508-900 Sa ˜o Paulo, SP, Brazil Tel/fax: +55 11 3091 7744; e-mail: sojancar@icb.usp.br Current Opinion in Nephrology and Hypertension 2009, 18:21–27 Purpose of review Eicosanoids are products of arachidonic acid metabolism which have important roles in renal homeostasis and disease. In recent years the development of genetically modified animals and new drugs targeting eicosanoids producing enzymes and receptors has unveiled new roles for eicosanoids in kidney function. This review provides an overview of eicosanoid biosynthesis and receptors and discusses recent findings on their role in acute and chronic renal diseases and in renal transplantation. Recent findings Products of the cyclooxygenases, 5-lipoxygenase, and cytochrome P450 pathways of arachidonic acid metabolism act through distinct receptors presented at different segment of the nephron. Apart from its role in renal physiology and hemodynamic, eicosanoids actively participate in the pathogenesis of acute and chronic renal diseases and have immunoregulatory role in kidney transplantation. Summary The new discoveries on the role of eicosanoids in kidney functions and the development of drugs targeting eicosanoids synthesis or action should help to envisage novel therapeutic approaches for patients suffering from renal diseases. Keywords acute renal injury, eicosanoids, end-stage renal disease, hypertension, transplantation Curr Opin Nephrol Hypertens 18:21–27 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins 1062-4821 1062-4821 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/MNH.0b013e32831a9df7