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* Renal Division, Department of Medicine, and
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115
Omega-3 fatty acid docosahexaenoic acid is converted to potent resolvins (Rv) and protectin D1 (PD1), two newly identified families of natural mediators of resolution of inflammation. We report that, in response to bilateral ischemia/reperfusion injury, mouse kidneys produce D series resolvins (RvDs) and PD1. Administration of RvDs or PD1 to mice before the ischemia resulted in a reduction in functional and morphological kidney injury. Initiation of RvDs and RvD1 administration 10 min after reperfusion also resulted in protection of the kidney as measured by serum creatinine 24 and 48 h later. Interstitial fibrosis after ischemia/reperfusion was reduced in mice treated with RvDs. Both RvDs and PD1 reduced the number of infiltrating leukocytes and blocked TLR-mediated activation of macrophages. Thus, the renal production of Rv and protectins, a previously unrecognized endogenous anti-inflammatory response, may play an important role in protection against and resolution of acute kidney injury. These data may also have therapeutic implications for potentiation of recovery from acute kidney injury.
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 Senior Fellowship from the National Kidney Research Fund (to J.S.D.), Grants DK-73299 (to J.S.D.), DK-39773 (to J.V.B.), DK-38452 (to J.V.B.), GM-38765 (to C.N.S.), DK-074448 (to C.N.S.), and P50 DE-016191 (to S.H., Y.L., and C.N.S.) from the National Institutes of Health, and Grant 0535492 (to V.S.V.) from the American Heart Association.
2 Address correspondence and reprint requests to Dr. Jeremy S. Duffield, Renal Division, Brigham and Women’s Hospital, Harvard Institutes of Medicine, 5th Floor, 4 Blackfan Circle, Boston MA 02115; E-mail address: jduffield{at}rics.bwh.harvard.edu or Dr. Charles N. Serhan, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115. E-mail address: cnserhan{at}zeus.bwh.harvard.edu
3 J.S.D. and S.H. and both laboratories contributed equally to this work.
4 Abbreviations used in this paper: PMN, polymorphonuclear neutrophil; DHA, docosahexaenoic acid; I/R, ischemia/reperfusion; PD1, protectin D1, 10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid, also termed neuroprotectin D1 (NPD1) when produced in neural tissues (see Ref. 49 ); PLP, paraformaledhyde-L-lysine-periodate; AA, arachidonic acid; LDH, lactate dehydrogenase; LC, liquid chromatography; MS, mass spectrometer/spectrometry; PAS, periodic acid-Schiff; MPO, myeloperoxidase; Rv, resolvin; RvDs, Rv D series; RvD1, 7S,8,17S-trihydroxy-docosa-4Z,9E,11E,13Z,15E,19Z-hexanoic acid; RvD2, 7S,16,17S-trihydroxy-docasa-4Z,8E,10Z,12E,14E,19Z-hexanoic acid; RvD3, 4S,11,17S-treihydroxy-docasa-5,7E,9E,13Z,15E,19Z-hexanoic acid; RvD4, 4S,5,17S-trihydroxy-docosa-6E,8E,10Z,13Z,15E,19Z-hexanoic acid; RvD5, 7S,17S-dihydroxy-docosa-4Z,8E,10Z,13Z,15E,19Z-hexanoic acid; RvD6, 4S,17S-dihydroxy-docosa 5E,7Z,10Z,13Z,15E,19Z-hexanoic acid; LDH, lactate dehydrogenase.
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