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Brandon A. Kemp, Nancy L. Howell, John J. Gildea, Shetal H. Padia, Intrarenal Ghrelin Receptor Antagonism Prevents High-Fat Diet-Induced Hypertension in Male Rats, Endocrinology, Volume 155, Issue 7, 1 July 2014, Pages 2658–2666, https://doi.org/10.1210/en.2013-2177
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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-Arg1, D-Phe5, D-Trp7,9, Leu11]-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.
