Deficiency in the Formation of 20-Hydroxyeicosatetraenoic Acid Enhances Renal Ischemia-Reperfusion Injury.

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.

• Authors: Yoshikazu Muroya, Fan Fan, Kevin R Regner, John R Falck, Michael R Garrett, Luis A Juncos, Richard J Roman
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 26 Issue 10 Pg. 2460-9 (Oct 2015) ISSN: 1533-3450 [Electronic] United States
• PMID: 25644108 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 by the American Society of Nephrology.

Chemical References

• Hydroxyeicosatetraenoic Acids
• 20-hydroxy-5,8,11,14-eicosatetraenoic acid
• Cytochrome P-450 CYP4A

Topics

• Acute Kidney Injury (etiology)
• Animals
• Cytochrome P-450 CYP4A (genetics)
• Gene Expression Regulation
• Genetic Predisposition to Disease
• Hydroxyeicosatetraenoic Acids (biosynthesis, deficiency, genetics)
• Kidney (blood supply, metabolism)
• Male
• Rats
• Rats, Sprague-Dawley
• Reperfusion Injury (complications, etiology)