Faculty Collaboration Database

Deficiency in the Formation of 20-Hydroxyeicosatetraenoic Acid Enhances Renal Ischemia-Reperfusion Injury. J Am Soc Nephrol 2015 Oct;26(10):2460-9

Date

02/04/2015

Pubmed ID

25644108

Pubmed Central ID

PMC4587700

DOI

10.1681/ASN.2014090868

Scopus ID

2-s2.0-84942938562 (requires institutional sign-in at Scopus site)   23 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 (±SEM) 24 hours after IR from 3.7±0.1 to 2.0±0.2 mg/dl in an SS.5(BN)-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.5(BN) rats. Similar results were observed in an SS.5(Lew)-congenic 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 by maintaining medullary blood flow and that a genetic deficiency in the formation of 20-HETE increases the susceptibility of SS rats to ischemic AKI.

Author List

Muroya Y, Fan F, Regner KR, Falck JR, Garrett MR, Juncos LA, Roman RJ

Author

Kevin R. Regner MD Interim Chair, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Acute Kidney Injury
Animals
Cytochrome P-450 CYP4A
Gene Expression Regulation
Genetic Predisposition to Disease
Hydroxyeicosatetraenoic Acids
Kidney
Male
Rats
Rats, Sprague-Dawley
Reperfusion Injury