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Acute Changes in Dietary -3 and -6 Polyunsaturated Fatty Acids Have a Pronounced Impact on Survival following Ischemic Renal Injury and Formation of Renoprotective Docosahexaenoic Acid-Derived Protectin D1¹

Iram R. Hassan^* and Karsten Gronert^2,*,

^* New York Medical College, Department of Pharmacology, Valhalla, NY 10595; and University of California, Berkeley, Center for Eye Disease and Development, School of Optometry, Berkeley, CA 94720

Exacerbated inflammation plays an important role in the pathogenesis of ischemic renal injury (IRI), which is the major cause of intrinsic acute renal failure. Clinical studies suggest that long-term treatment with -3 polyunsaturated fatty acids (PUFA) improves renal function and lowers the risk of death or end-stage renal disease. Docosahexaenoic acid, a principle -3 PUFA of fish oils, is of particular interest as it is found in most human tissues and is converted to protectin D1 (PD1), which exhibits antiinflammatory and proresolving bioactions. We set out to investigate the impact of acute dietary modulation of -3 or -6 PUFA on IRI and renal lipid autacoid circuits, using an established mouse model and liquid chromatography-mass spectroscopy/mass spectroscopy-based lipidomics. Thirty minutes of renal ischemia significantly elevated serum creatinine in the -6 diet group while renal function remained normal in the matched -3 diet group. Notably, extending ischemia to 45 min caused 100% mortality in the -6 group, in sharp contrast to 0% mortality in the -3 group. Protection against IRI in the -3 group correlated with decreased polymorphonuclear leukocyte recruitment, chemokine and cytokine levels, abrogated formation of lipoxygenase- and cyclooxygenase-derived eicosanoids, and increased renal levels of PD1. Systemic treatment with PD1 reduced kidney polymorphonuclear leukocyte influx and, more importantly, amplified renoprotective heme-oxygenase-1 protein and mRNA expression in injured and uninjured kidneys. These findings suggest therapeutic or dietary amplification of PD1 circuits restrains acute renal injury and that short-term changes in dietary -3 and -6 PUFA dramatically impacts renal lipid autacoid formation and outcome of IRI.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by a grant from the National Eye Institutes (EY0116136; to K.G.) and a Pharmaceutical Research and Manufacturers of America Foundation Predoctoral Fellowship (to I.R.H.).

² Address correspondence and reprint requests to Dr. Karsten Gronert, Center for Eye Disease and Development, School of Optometry, Minor Hall 594, MC 2020, University of California at Berkeley, Berkeley, CA 94720-2020. E-mail: kgronert{at}berkeley.edu

³ Abbreviations used in this paper: ARF, acute renal failure; AA, arachidonic acid; ATLa, aspirin-triggered 15-epi-16-p-fluorophenoxy-LXA₄; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; GC/MS, gas chromatography/mass spectroscopy; HETE, hydroxyeicosatetraenoic acid; HO, heme-oxygenase; IRI, ischemic renal injury; LC-MS/MS, liquid chromatography-mass spectroscopy/mass spectroscopy; LOX, lipoxygenase; LXA₄, lipoxin A₄; MPO, myeloperoxidase; PD1, protectin D1; PMN, polymorphonuclear leukocyte; PUFA, polyunsaturated fatty acid; Rv, resolvin; 17S-HDHA, 17S-hydroxy-docosa-4Z,7Z,11Z,13Z,15E,19Z-hexaenoic acid.

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