Role of γ melanocyte-stimulating hormone–renal melanocortin 3 receptor system in blood pressure regulation in salt-resistant and salt-sensitive rats

Abstract

Melanocortin 3 receptor (MC3-R) has high affinity and specificity to γ melanocyte-stimulating hormone ( γMSH), a natriuretic peptide involved in regulation of blood pressure (BP) and sodium excretion. Recent studies showing increased MC3-R expression and elevated plasma γMSH 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 γMSH 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 γMSH and a 2-fold increase in renal MC3-R in DSR rats. Plasma γMSH 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 γMSH–renal MC3-R pathway is activated and appears to be biologically functional in the DSS rats.