Genetic disruption of γ-melanocyte–stimulating hormone signaling leads to salt-sensitive hypertension in the mouse

Abstract

IntroductionNumerous neural and humoral systems interact to control total body sodium content, body fluid volumes, and blood pressure through the regulation of urinary sodium excretion (U Na V). These include antinatriuretic pathways such as the renin-angiotensin system, aldosterone and sympathetic nerve activity to the kidneys, and natriuretic pathways such as the natriuretic peptide system (1, 2). Recent evidence has indicated that other natriuretic systems are involved in regulating U Na V, including dopaminergic activity, the kallikrein-kinin system, and other peptide hormonal pathways (2-4). Among these, evidence has been presented that the natriuretic peptide γ-melanocyte-stimulating hormone (γ-MSH) participates in the integrated response to a high intake of dietary sodium: rats ingesting a high-sodium diet (HSD) for 1 week or longer have a marked increase in plasma γ-MSH concentration as well as an increase in the content of γ-MSH in the neurointermediate lobe (NIL) of the The γ-melanocyte-stimulating hormone (γ-MSH) is a natriuretic peptide derived from the N-terminal region of proopiomelanocortin (POMC). Evidence suggests that it may be part of the coordinated response to a low-sodium diet (LSD). We tested the effect of the HSD (8% NaCl) compared with LSD (0.07%) on mean arterial pressure (MAP) in mice with targeted disruption of the PC2 gene (PC2 -/-), necessary for processing of POMC into γ-MSH, or the melanocortin receptor 3 gene (Mc3r -/-; the receptor for MSH). In wild-type mice, HSD for 1 week did not alter MAP versus LSD mice, but plasma γ-MSH immunoreactivity was more than double the LSD value. In contrast, in PC2 -/-mice, MAP on the LSD was not greater than in wild-type mice, but plasma γ-MSH was reduced to one-seventh the wild-type value. On the HSD, MAP rose to a markedly hypertensive level while plasma γ-MSH concentration remained severely depressed. Intravenous infusion of γ-MSH (0.2 pmol/min) for 30 min to PC2 -/-mice after 1 week of HSD lowered MAP from hypertensive levels to normal; infusion of α-MSH at the same rate had no effect. Injection of 60 fmol of γ-MSH into the lateral cerebral ventricle of hypertensive mice also lowered MAP to normal. Administration of a stable analogue of γ-MSH intra-abdominally by microosmotic pump to PC2 -/-mice prevented the development of hypertension when ingesting the HSD. In mice with targeted disruption of the Mc3r gene, the HSD also led to marked hypertension accompanied by elevated plasma levels of γ-MSH; infusion of exogenous γ-MSH to these mice had no effect on MAP. These results strongly suggest that PC2-dependent processing of POMC into γ-MSH is necessary for the normal response to the HSD. γ-MSH deficiency results in marked salt-sensitive hypertension that is rapidly improved with exogenous γ-MSH through a central site of action. α-MSH infused at the same rate had no effect on MAP, indicating that the hypertension is a specific consequence of impaired POMC processing into γ-MSH. Absence of Mc3r produces γ-MSH resistance and hypertension on the H...

Salt feedback on the renin-angiotensin-aldosterone system

“…In general, salt and water homeostasis of the body is controlled by a bunch of neurohumoral factors. Some of these factors, such as vasopressin, oxytocin, melanocyte-stimulating hormone, uroguanylin, and the cardiac natriuretic peptides ANP and B-type natriuretic peptide (BNP), circulate in the plasma and are regulated by the salt intake [4,6,63,79,82,87] and, therefore, might be involved in the salt-dependent regulation of the renin system. In fact, the ANP appears to be the most ls ls + ACEI ctrl g g g Fig.…”

Biphasic Effect of Melanocortin Agonists on Metabolic Rate and Body Temperature

“…MC1R agonism causes darkening of skin and hair (Robbins et al, 1993) and reduces inflammation (Leoni et al, 2010; Li and Taylor, 2008) while loss of MC1R function reduces sensitivity to certain painful stimuli (Mogil et al, 2005; Mogil et al, 2003). MC3R contributes to the control of energy homeostasis (e.g., null mice are mildly obese (Butler et al, 2000; Chen et al, 2000a)), natriuresis (Ni et al, 2003), and inflammation, acting at least partially on macrophages (Getting et al, 2008). Genetic variation in MC3R may contribute to human obesity (Feng et al, 2005; Renquist et al, 2011).…”

Defective Neuropeptide Processing and Ischemic Brain Injury: A Study on Proprotein Convertase 2 and its Substrate Neuropeptide in Ischemic Brains

“…PC2-null mice also exhibit vulnerability, or lack of response to certain stresses. Ni et al (2003) have reported that after mild salt loading, PC2-null mice develop hypertension, which is not seen in wild-type mice, because of the lack of γ -MSH. Croissandeau et al (2006), on the contrary, have observed enhanced analgesia toward mechanical or thermal nociceptive stimuli in PC2-null mice.…”