title: 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: Departments of Pharmacology and Toxicology and.
authors: Yoshikazu
authors: Y
authors: Muroya
authors: Departments of Pharmacology and Toxicology and.
authors: Fan
authors: F
authors: Fan
authors: Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; and.
authors: Kevin R
authors: KR
authors: Regner
authors: Department of Biochemistry, University of Texas Southwestern, Dallas, Texas.
authors: John R
authors: JR
authors: Falck
authors: Departments of Pharmacology and Toxicology and.
authors: Michael R
authors: MR
authors: Garrett
authors: Medicine, University of Mississippi Medical Center, Jackson, Mississippi;
authors: Luis A
authors: LA
authors: Juncos
authors: Departments of Pharmacology and Toxicology and rroman@umc.edu.
authors: Richard J
authors: RJ
authors: Roman
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology; D000818:Animals; D042926:Cytochrome P-450 CYP4A / Q000235:genetics; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000150:complications / Q000209:etiology*
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D042926:Cytochrome P-450 CYP4A
keywords: 20-HETE; AKI; genetics; intrarenal blood flow
references: Am J Physiol Renal Physiol. 2000 Apr;278(4):F667-75
references: 10751229
references: Am J Physiol Regul Integr Comp Physiol. 2012 May 15;302(10):R1209-18
references: 22442195
references: Am J Physiol Regul Integr Comp Physiol. 2001 Sep;281(3):R730-7
references: 11506986
references: Physiol Rev. 2002 Jan;82(1):131-85
references: 11773611
references: Physiol Genomics. 2002 Feb 28;8(2):81-6
references: 11875185
references: Am J Physiol Renal Physiol. 2003 Mar;284(3):F474-9
references: 12419775
references: Hypertens Res. 2003 Nov;26(11):929-36
references: 14714586
references: Kidney Int. 2004 Jun;65(6):2201-11
references: 15149333
references: Circ Res. 1984 Mar;54(3):313-22
references: 6421507
references: Am J Pathol. 1984 Aug;116(2):253-61
references: 6465286
references: J Am Soc Nephrol. 2013 Jan;24(1):37-42
references: 23222124
references: Kidney Int. 2013 Feb;83(2):242-50
references: 23235564
references: Prostaglandins Other Lipid Mediat. 2013 Apr-May;102-103:42-8
references: 23500064
references: PLoS One. 2013;8(12):e82482
references: 24324797
references: J Am Soc Nephrol. 2014 Dec;25(12):2689-701
references: 24925726
references: J Hypertens. 1995 May;13(5):557-66
references: 7561014
references: N Engl J Med. 1996 May 30;334(22):1448-60
references: 8618585
references: Hypertension. 1998 Jan;31(1 Pt 2):225-31
references: 9453307
references: Am J Physiol. 1998 Oct;275(4 Pt 2):F595-604
references: 9755131
references: Hypertension. 1999 Jan;33(1 Pt 2):419-23
references: 9931140
references: Circulation. 2005 Jan 4;111(1):63-9
references: 15611369
references: J Pharmacol Exp Ther. 2005 Jun;313(3):1289-95
references: 15769866
references: Hypertension. 2005 Oct;46(4):766-71
references: 16144986
references: J Am Soc Nephrol. 2005 Nov;16(11):3365-70
references: 16177006
references: J Am Soc Nephrol. 2006 Jun;17(6):1503-20
references: 16707563
references: Nephrol Dial Transplant. 2007 Feb;22(2):342-6
references: 17132706
references: Hypertension. 2007 Mar;49(3):687-94
references: 17210834
references: Am J Physiol Renal Physiol. 2007 Jul;293(1):F342-9
references: 17442729
references: Clin J Am Soc Nephrol. 2007 Mar;2(2):356-65
references: 17699435
references: Am J Physiol Heart Circ Physiol. 2007 Dec;293(6):H3542-9
references: 17890422
references: Br J Pharmacol. 2001 Jun;133(3):325-9
references: 11375247
references: Virchows Arch A Pathol Anat Histopathol. 1986;409(4):535-42
references: 3090776
references: Hypertension. 1989 May;13(5):440-8
references: 2524442
references: Hypertension. 1996 Mar;27(3 Pt 2):564-8
references: 8613204
references: J Am Soc Nephrol. 2008 Apr;19(4):714-21
references: 18235092
references: Endocrine. 2008 Apr;33(2):215-22
references: 18484194
references: Am J Physiol Renal Physiol. 2008 Sep;295(3):F837-42
references: 18653478
references: Am J Physiol Renal Physiol. 2008 Dec;295(6):F1764-77
references: 18842817
references: Kidney Int. 2009 Mar;75(5):511-7
references: 19052533
references: J Biosci Bioeng. 2010 Jun;109(6):526-30
references: 20471588
references: Proc Natl Acad Sci U S A. 2010 Sep 28;107(39):17017-22
references: 20837537
references: Kidney Int. 2011 Jan;79(1):57-65
references: 20962739
references: Kidney Int. 2011 Jan;79(1):10-3
references: 21157458
references: Curr Opin Nephrol Hypertens. 2012 Jan;21(1):33-8
references: 22080855
references: Nephrol Dial Transplant. 2012 Jan;27(1):136-45
references: 21680852
references: Hypertension. 2008 Mar;51(3):767-72
references: 18227405