Deficiency in the formation of 20-Hydroxyeicosatetraenoic acid enhances renal ischemia-reperfusion injury

Yoshikazu Muroya, Fan Fan, Kevin R. Regner, J R Falck, Michael R. Garrett, Luis A. Juncos, Richard J. Roman

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Ischemia-reperfusion (IR) injury is the most common cause of AKI. The susceptibility to develop AKI varies widely among patients. However, little is known about the genes involved. 20-Hydroxyeicosatetraenoic acid (20-HETE) has an important role in the regulation of renal tubular and vascular function and has been implicated in IR injury. In this study, we examined whether a deficiency in the renal formation of 20-HETE enhances the susceptibility of Dahl salt-sensitive (SS) rats to ischemic AKI. Transfer of chromosome 5 containing the CYP4A genes responsible for the formation of 20-HETE from the Brown Norway (BN) rat onto the SS genetic background increased renal 20-HETE levels after ischemia and reduced plasma creatinine levels (6SEM) 24 hours after IR from 3.760.1 to 2.060.2 mg/dl in an SS.5BN-consomic strain. Transfer of this chromosome also prevented the secondary decline in medullary blood flow and ischemia that develops 2 hours after IR in the susceptible SS strain. Blockade of the synthesis of 20-HETE with HET0016 reversed the renoprotective effects in SS.5BN rats. Similar results were observed in an SS.5Lewcongenic strain, in which a smaller region of chromosome 5 containing the CYP4A genes from a Lewis rat was introgressed onto the SS genetic background. These results indicate that 20-HETE has a protective role in renal IR injury bymaintaining medullary blood flow and that a genetic deficiency in the formation of 20-HETE increases the susceptibility of SS rats to ischemic AKI.

Original languageEnglish (US)
Pages (from-to)2460-2469
Number of pages10
JournalJournal of the American Society of Nephrology
Volume26
Issue number10
DOIs
StatePublished - Oct 1 2015

ASJC Scopus subject areas

  • Nephrology

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