title: Role of 20-HETE in the antihypertensive effect of transfer of chromosome 5 from Brown Norway to Dahl salt-sensitive rats.
abstract: This study examined whether substitution of chromosome 5 containing the CYP4A genes from Brown Norway rat onto the Dahl S salt-sensitive (SS) genetic background upregulates the renal production of 20-HETE and attenuates the development of hypertension. The expression of CYP4A protein and the production of 20-HETE were significantly higher in the renal cortex and outer medulla of SS.5(BN) (chromosome 5-substituted Brown Norway rat) consomic rats fed either a low-salt (LS) or high-salt (HS) diet than that seen in SS rats. The increase in the renal production of 20-HETE in SS.5(BN) rats was associated with elevated expression of CYP4A2 mRNA. MAP measured by telemetry rose from 117 ± 1 to 183 ± 5 mmHg in SS rats fed a HS diet for 21 days, but only increased to 151 ± 5 mmHg in SS.5(BN) rats. The pressure-natriuretic and diuretic responses were twofold higher in SS.5(BN) rats compared with SS rats. Protein excretion rose to 354 ± 17 mg/day in SS rats fed a HS diet for 21 days compared with 205 ± 13 mg/day in the SS.5(BN) rats, and the degree of glomerular injury was reduced. Baseline glomerular capillary pressure (Pgc) was similar in SS.5(BN) rats (43 ± 1 mmHg) and Dahl S (44 ± 2 mmHg) rats. However, Pgc increased to 59 ± 3 mmHg in SS rats fed a HS diet for 7 days, while it remained unaltered in SS.5(BN) rats (43 ± 2 mmHg). Chronic administration of an inhibitor of the synthesis of 20-HETE (HET0016, 10 mg·kg(-1)·day(-1) iv) reversed the antihypertensive phenotype seen in the SS.5(BN) rats. These findings indicate that the transfer of chromosome 5 from the BN rat onto the SS genetic background increases the renal expression of CYP4A protein and the production of 20-HETE and that 20-HETE contributes to the antihypertensive and renoprotective effects seen in the SS.5(BN) consomic strain.
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Williams
authors.forename: Fan
authors.initials: F
authors.lastname: Fan
authors.forename: Sydney
authors.initials: S
authors.lastname: Murphy
authors.forename: Carlos
authors.initials: C
authors.lastname: Schreck
authors.forename: Jozef
authors.initials: J
authors.lastname: Lazar
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Jacob
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Roman
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D042926:Cytochrome P-450 CYP4A / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control*; D007668:Kidney / Q000098:blood supply / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN / Q000235:genetics*; D020303:Rats, Inbred Dahl / Q000235:genetics*; D013997:Time Factors
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; D012333:RNA, Messenger; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D042926:Cytochrome P-450 CYP4A