PMID- 31349026 OWN - NLM STAT- MEDLINE DCOM- 20200302 LR - 20220311 IS - 1879-2618 (Electronic) IS - 1388-1981 (Print) IS - 1388-1981 (Linking) VI - 1864 IP - 11 DP - 2019 Nov TI - A dual role of 12/15-lipoxygenase in LPS-induced acute renal inflammation and injury. PG - 1669-1680 LID - S1388-1981(19)30129-5 [pii] LID - 10.1016/j.bbalip.2019.07.009 [doi] AB - Recent studies suggest a potential role of bioactive lipids in acute kidney injury induced by lipopolysaccharide (LPS). The current study was designed to determine the profiling activities of various polyunsaturated fatty acid (PUFA) metabolizing enzymes, including lipoxygenases (LO), cyclooxygenase, and cytochrome P450 in the plasma of LPS-injected mice using LC-MS. Heat map analysis revealed that out of 126 bioactive lipids screened, only the 12/15-LO metabolite, 12-HETE, had a significant (2.24 +/- 0.4) fold increase relative to control (P = 0.0001) after Bonferroni Correction (BCF alpha = 0.003). We then determined the role of the 12/15-LO in LPS-induced acute kidney injury using genetic and pharmacological approaches. Treatment of LPS injected mice with the 12/15-LO inhibitor, baicalein, significantly reduced levels of renal injury and inflammation markers including urinary thiobarbituric acid reactive substance (TBARs), urinary monocyte chemoattractant protein-1 (MCP-1), renal interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha). Similarly, knocking-out of 12/15-LO reduced levels of renal inflammation and injury markers elicited by LPS injection. Next, we tested whether exogenous supplementation with docosahexaenoic acid (DHA) as a substrate would divert the role of 12/15-LO from being pro-inflammatory to anti-inflammatory via increased production of the anti-inflammatory metabolite. DHA treatment restored the decreased in plasma level of resolvin D2 (RvD2) and reduced renal injury in LPS-injected mice whereas DHA treatment failed to provide any synergistic effects in reducing renal injury in LPS injected 12/15-LO knock-out mice. The ability of RvD2 to protect kidney against LPS-induced renal injury was further confirmed by exogenous RvD2 which significantly reduced the elevation in renal injury in LPS injected mice. These data suggest a double-edged sword role of 12/15-LO in LPS-induced acute renal inflammation and injury, depending on the type of substrate available for its activity. CI - Copyright (c) 2019 Elsevier B.V. All rights reserved. FAU - Elmarakby, Ahmed A AU - Elmarakby AA AD - Department of Oral Biology and Diagnostic Sciences, Augusta University, Augusta, GA, USA; Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, Egypt. Electronic address: aelmarakby@augusta.edu. FAU - Ibrahim, Ahmed S AU - Ibrahim AS AD - Department of Oral Biology and Diagnostic Sciences, Augusta University, Augusta, GA, USA; Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt; Wayne State University, Department of Ophthalmology, Visual, and Anatomical Sciences, Department of Pharmacology, Detroit, MI. FAU - Katary, Mohamed A AU - Katary MA AD - Department of Oral Biology and Diagnostic Sciences, Augusta University, Augusta, GA, USA; Department of Pharmacology, Faculty of Pharmacy, Damnhour University, Egypt. FAU - Elsherbiny, Nehal M AU - Elsherbiny NM AD - Department of Oral Biology and Diagnostic Sciences, Augusta University, Augusta, GA, USA; Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt. FAU - El-Shafey, Mohamed AU - El-Shafey M AD - Department of Oral Biology and Diagnostic Sciences, Augusta University, Augusta, GA, USA; Department of Anatomy, Faculty of Medicine, Mansoura University, Mansoura, Egypt. FAU - Abd-Elrazik, Ahmed M AU - Abd-Elrazik AM AD - Department of Oral Biology and Diagnostic Sciences, Augusta University, Augusta, GA, USA. FAU - Abdelsayed, Rafik A AU - Abdelsayed RA AD - Department of Oral Biology and Diagnostic Sciences, Augusta University, Augusta, GA, USA. FAU - Maddipati, Krishna Rao AU - Maddipati KR AD - Department of Pathology, Wayne State University, Detroit, MI, USA. FAU - Al-Shabrawey, Mohamed AU - Al-Shabrawey M AD - Department of Oral Biology and Diagnostic Sciences, Augusta University, Augusta, GA, USA; Department of Anatomy, Faculty of Medicine, Mansoura University, Mansoura, Egypt; Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, USA. Electronic address: malshabrawey@augusta.edu. LA - eng GR - R01 EY023315/EY/NEI NIH HHS/United States GR - S10 RR027926/RR/NCRR NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20190723 PL - Netherlands TA - Biochim Biophys Acta Mol Cell Biol Lipids JT - Biochimica et biophysica acta. Molecular and cell biology of lipids JID - 101731727 RN - 0 (12-15-lipoxygenase) RN - 0 (Lipopolysaccharides) RN - EC 1.13.11.31 (Arachidonate 12-Lipoxygenase) RN - EC 1.13.11.33 (Arachidonate 15-Lipoxygenase) SB - IM MH - Acute Kidney Injury/*immunology/pathology MH - Animals MH - Arachidonate 12-Lipoxygenase/*immunology MH - Arachidonate 15-Lipoxygenase/*immunology MH - Inflammation/*immunology/pathology MH - Lipopolysaccharides/*immunology MH - Male MH - Mice, Inbred C57BL PMC - PMC6750989 MID - NIHMS1537175 OTO - NOTNLM OT - 12/15-lipoxygenase OT - Baicalein OT - DHA OT - Inflammation OT - LPS OT - Renal injury OT - Resolvin EDAT- 2019/07/28 06:00 MHDA- 2020/03/03 06:00 PMCR- 2020/11/01 CRDT- 2019/07/27 06:00 PHST- 2019/02/11 00:00 [received] PHST- 2019/06/17 00:00 [revised] PHST- 2019/07/19 00:00 [accepted] PHST- 2019/07/28 06:00 [pubmed] PHST- 2020/03/03 06:00 [medline] PHST- 2019/07/27 06:00 [entrez] PHST- 2020/11/01 00:00 [pmc-release] AID - S1388-1981(19)30129-5 [pii] AID - 10.1016/j.bbalip.2019.07.009 [doi] PST - ppublish SO - Biochim Biophys Acta Mol Cell Biol Lipids. 2019 Nov;1864(11):1669-1680. doi: 10.1016/j.bbalip.2019.07.009. Epub 2019 Jul 23.