title: Intrarenal ghrelin receptor antagonism prevents high-fat diet-induced hypertension in male rats.
abstract: Excess weight gain contributes up to 65% of the risk of primary hypertension, and the increase in blood pressure in response to high-fat diet (HFD) is preceded by significant increases in renal tubular sodium (Na(+)) reabsorption. In normal rats, intrarenal ghrelin infusion increases distal nephron-dependent Na(+) reabsorption via activation of the intrarenal ghrelin receptor (GHSR). This study focusses on the role of intrarenal GHSR-mediated Na(+) reabsorption in HFD-induced hypertension. Dahl salt-sensitive rats received standard diet or HFD for 6 weeks. Rats underwent uninephrectomy and osmotic minipump implantation for chronic intrarenal delivery of vehicle (0.25 μL/h × 28 d), selective GHSR antagonist [D-Lys-3]-growth hormone releasing peptide-6 (0.2μM/d), or GHSR inverse agonist [D-Arg(1), D-Phe(5), D-Trp(7,9), Leu(11)]-substance P (SUB-P) (3.6μM/d). HFD rats with vehicle pumps had significantly increased renal GHSR expression compared with standard diet (0.092 ± 0.005 vs 0.065 ± 0.004 arbitrary units; P < .05), whereas acyl ghrelin levels were similar (16.3±6.2 vs 15.7±8.7 pg/g tissue). HFD rats with vehicle pumps became hypertensive after 2 weeks (P < .05) and showed a significant reduction in 24-hour urine Na(+) before hypertension. At this time, these rats showed an increase in collecting duct α-epithelial Na(+) channel, thereby providing a potential mechanism for the excess Na(+) reabsorption. In contrast, HFD rats with [D-Lys-3]-growth hormone releasing peptide-6 or SUB-P pumps never became hypertensive and did not show the reduction in urine Na(+). Because SUB-P blocks the constitutive, but not ghrelin-dependent, activity of the GHSR, and HFD-induced α-epithelial Na(+) channel up-regulation was abolished during GHSR antagonism, these data suggest that HFD increases the constitutive activity of renal GHSR to increase Na(+) reabsorption and induce hypertension in rats.
authors.affiliation: Division of Endocrinology and Metabolism (B.A.K., N.L.H., S.H.P.), Department of Medicine, and Department of Pathology (J.J.G.), University of Virginia School of Medicine, Charlottesville, Virginia 22908-1414.
authors.forename: Brandon A
authors.initials: BA
authors.lastname: Kemp
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Howell
authors.forename: John J
authors.initials: JJ
authors.lastname: Gildea
authors.forename: Shetal H
authors.initials: SH
authors.lastname: Padia
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects*; D004435:Eating / Q000187:drug effects; D054439:Ghrelin / Q000378:metabolism; D006973:Hypertension / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000601:surgery; D008297:Male; D009392:Nephrectomy; D009842:Oligopeptides / Q000494:pharmacology; D051381:Rats; D020303:Rats, Inbred Dahl; D017207:Rats, Sprague-Dawley; D054440:Receptors, Ghrelin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012964:Sodium / Q000378:metabolism / Q000493:pharmacokinetics / Q000652:urine; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors
chemical_list: C520836:GHRP-6, Lys(3)-; D054439:Ghrelin; D009842:Oligopeptides; D054440:Receptors, Ghrelin; D013373:Substance P; C045800:substance P, Phe(5)-Trp(7,9)-Leu(11)-; D012964:Sodium