Role of gamma melanocyte-stimulating hormone-renal melanocortin 3 receptor system in blood pressure regulation in salt-resistant and salt-sensitive rats.
Melanocortin 3 receptor (MC3-R) has high affinity and specificity to gamma melanocyte-stimulating hormone (gammaMSH), a natriuretic peptide involved in regulation of blood pressure (BP) and sodium excretion. Recent studies showing increased MC3-R expression and elevated plasma gammaMSH in normal rats fed a high-salt diet support the role of this system in sodium homeostasis. We hypothesized that dysregulation of MC3-R response to dietary salt may contribute to salt retention and BP elevation in salt-sensitive hypertension. We examined renal MC3-R expression, plasma gammaMSH concentration, and response to MC3-R agonist and antagonist in Dahl salt-sensitive (DSS) and Dahl salt-resistant (DSR) rats fed high-salt (8%) or low-salt (0.07%) diets for 3 weeks. Consumption of high-salt diet significantly increased BP in the DSS but not the DSR group. High-salt diet led to a 5-fold increase in plasma gammaMSH and a 2-fold increase in renal MC3-R in DSR rats. Plasma gammaMSH and renal MC3-R abundance in DSS rats were maximally elevated on low-salt diet and remained unchanged on high-salt diet. Administration of MC3-R agonist melanotan II significantly lowered BP and raised fractional Na excretion in the DSR but not the DSS rats consuming high-salt diet. In contrast, MC3-R antagonist SHU9119 significantly raised BP and lowered fractional Na excretion in both groups. Thus, the data suggest that gammaMSH-renal MC3-R pathway is activated and appears to be biologically functional in the DSS rats.
Chandramohan
Gangadarshni
G
Division of Pediatric Nephrology, Los Angeles Biomedical Research Insititute at Harbor-UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Durham
Nicquanna
N
Sinha
Satyesh
S
Norris
Keith
K
Vaziri
Nosratola D
ND
D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D015153:Blotting, Western; D003404:Creatinine / Q000097:blood; D015536:Down-Regulation; D007668:Kidney / Q000378:metabolism*; D008297:Male; D011507:Proteinuria / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D020303:Rats, Inbred Dahl; D044104:Receptor, Melanocortin, Type 3 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D012964:Sodium / Q000378:metabolism; D012982:Sodium, Dietary / Q000494:pharmacology; D013686:Telemetry; D019825:gamma-MSH / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*
D044104:Receptor, Melanocortin, Type 3; D012982:Sodium, Dietary; D019825:gamma-MSH; D012964:Sodium; D003404:Creatinine