In various mammalian species, including humans, water restriction leads to an acute increase in urinary sodium excretion. This process, known as dehydration natriuresis, helps prevent further accentuation of hypernatremia and the accompanying rise in extracellular tonicity. Serum-and glucocorticoid-inducible kinase (Sgk1), which is expressed in the renal medulla, is regulated by extracellular tonicity. However, the mechanism of its regulation and the physiological role of hypertonicity-induced SGK1 gene expression remain unclear. Here, we identified a tonicity-responsive enhancer (TonE) upstream of the rat Sgk1 transcriptional start site. The transcription factor NFAT5 associated with TonE in a tonicity-dependent fashion in cultured rat renal medullary cells, and selective blockade of NFAT5 activity resulted in suppression of the osmotic induction of the Sgk1 promoter. In vivo, water restriction of rats or mice led to increased urine osmolality, increased Sgk1 expression, increased expression of the type A natriuretic peptide receptor (NPR-A), and dehydration natriuresis. In cultured rat renal medullary cells, siRNA-mediated Sgk1 knockdown blocked the osmotic induction of natriuretic peptide receptor 1 (Npr1) gene expression. Furthermore, Npr1 -/-mice were resistant to dehydration natriuresis, which suggests that Sgk1-dependent activation of the NPR-A pathway may contribute to this response. Collectively, these findings define a specific mechanistic pathway for the osmotic regulation of Sgk1 gene expression and suggest that Sgk1 may play an important role in promoting the physiological response of the kidney to elevations in extracellular tonicity. IntroductionPersistent hypertonicity, typically reflecting a high extracellular sodium concentration, stresses mammalian cells due to the ensuing osmotic efflux of water that shrinks the cells and concentrates their contents. Under most conditions, the concentration of extracellular sodium in mammals is controlled primarily through regulation of water metabolism. As extracellular sodium and plasma tonicity rise, the thirst mechanism is activated, and secretion of the neurohypophyseal hormone vasopressin into plasma increases. Vasopressin binds to its cognate receptors in the collecting duct of the kidney, resulting in increased water retention.Following short-term water restriction, several mammals demonstrate an acute increase in urinary sodium excretion that is independent of changes in water metabolism. This response, termed dehydration natriuresis (1-11), plays an important role in preventing further accentuation of hypernatremia and the accompanying rise in extracellular tonicity. A similar natriuresis is seen following infusion of hypertonic saline (12). Investigations to date have suggested a role for central versus peripheral osmoreceptors and blood-borne versus neural effectors in contributing to dehydration-induced natriuresis; however, the precise mechanism(s) underlying this natriuresis remains undefined.
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...
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...
-␥-Melanocyte stimulating hormone (␥-MSH) is a circulating natriuretic peptide hormone derived from proopiomelanocortin (POMC); its concentration in plasma and pituitary POMC mRNA abundance, increase in rats ingesting a high-sodium diet (HSD, 8% NaCl) compared with a low-sodium diet (LSD, 0.07% NaCl). RT-PCR of rat kidney RNA demonstrated reaction products of the expected size in both cortex and medulla for MC3-R, MC4-R, and MC5-R mRNA; no signal for MC1-R or MC2-R was detected. Relative to -actin or cyclophilin, abundance of the three receptor transcripts after 1 wk of the LSD was approximately equal in both cortex and medulla. After 1 wk of the HSD, mRNA abundance of MC4-R and MC5-R was unchanged, whereas that of MC3-R in medulla more than doubled, the ratio of MC3-R/-actin signal increasing from 0.38 Ϯ 0.04 on LSD to 0.84 Ϯ 0.04 on HSD (P Ͻ 0.001). No significant increase occurred in the cortex. The increase in MC3-R expression induced by dietary sodium was observed in inner medullary collecting duct (IMCD) cells isolated from the kidneys of HSD rats, suggesting that these cells were the major site of receptor expression in the medulla. Immunoblots of whole medullary and IMCD cell homogenates detected MC3-R immunoreactive protein; its expression was twice as great in samples from HSD vs. LSD rat kidneys, paralleling the increase in MC3-R mRNA abundance on the HSD. No changes in MC4-R or MC5-R protein expression were observed. Incubation of IMCD cell suspensions with increasing concentrations of ␥ 2-MSH led to increased cAMP accumulation, with values from rats on the HSD being roughly double the values from LSD rats. Intrarenal infusion of ␥ 2-MSH (500 fmol/min) increased sodium and cAMP excretion from the infused but not contralateral kidney of HSD rats, while having no effect in LSD rats. These data show that MC3-R is expressed in rat IMCD cells in a manner modulated by dietary sodium intake. Because MC3-R is the receptor with which ␥-MSH interacts, our findings suggest the existence of a sodium-regulating system, activated in response to a HSD, which increases urinary sodium excretion to balance the high-sodium intake.␥-melanocyte stimulating hormone; sodium excretion; inner medullary collecting duct; peptide hormone; sodium balance; cyclic AMP ⌫-MELANOCYTE STIMULATING HORMONE (␥-MSH) is a natriuretic peptide derived, like ␣-and -MSH, from processing of proopiomelancortin (POMC) in the pituitary intermediate lobe (IL) from which it is secreted into the circulation (1, 9, 29). Three forms of ␥-MSH have been identified: ␥ 1 -MSH has 11 amino acids with a COOH-terminal amidation, ␥ 2 -MSH is identical to ␥ 1 -MSH but with a COOH-terminal glycine added, and ␥ 3 -MSH has an additional COOH-terminal extension of 13 amino acids; these structural differences have been suggested to underlie differing actions of the ␥-MSH peptides (10,31,34). MSH peptides exert their functions by interacting with a family of five transmembrane melanocortin receptors, termed MC1-R to MC5-R, which are linked to adenylate cyclase and...
Abstract-␥-Melanocyte-stimulating hormone (␥-MSH) is a natriuretic peptide derived from proopiomelanocortin (POMC) in the pituitary neurointermediate lobe (NIL); its plasma concentration in rats doubles after ingestion of a high (HSD; 8% NaCl) compared with a low sodium diet (LSD; 0.07%). Because NIL function is regulated through dopaminergic pathways, we asked whether dopaminergic stimulation with bromocriptine (5 mg/kg IP daily for 1 week) or inhibition with haloperidol (5 mg/kg IP for 1 week) alters the ␥-MSH response to a HSD. In vehicle-treated rats, plasma ␥-MSH and NIL ␥-MSH content on the HSD were both markedly elevated over values in rats on the LSD (PϽ0.001); no difference in mean arterial pressure (MAP) occurred. In haloperidol-treated rats on the LSD, both plasma ␥-MSH and NIL ␥-MSH content were greater than in vehicle-treated rats (PϽ0.05) and did not increase further on the HSD; MAP was also no different. In bromocriptine-treated rats, neither plasma ␥-MSH nor NIL ␥-MSH content increased on the HSD versus LSD, and MAP was markedly elevated on the HSD ( Key Words: natriuretic peptides Ⅲ pituitary Ⅲ hypertension, sodium-dependent Ⅲ dopamine M elanocyte-stimulating hormones (MSHs) are peptides of ␣, , and ␥ primary structure, which are derived from the ACTH/-endorphin precursor proopiomelanocortin (POMC). Identified initially from the property of ␣-and -MSH to induce melanin dispersion in melanocytes of fish and amphibians, they are highly conserved in mammalian species, where their pigmentary function is minor. This has suggested that they may serve other important biological functions, and roles in inflammation, temperature regulation, satiety, and cardiovascular control have all been indicated. [1][2][3][4] Each of the MSH peptides is also natriuretic, 5-8 and the plasma concentration and pituitary content of ␥-MSH immunoreactivity increase in rats fed a high sodium diet (HSD). 9,10 Additional support for a role in sodium homeostasis comes from the observations that an HSD increases the mRNA abundance of POMC and of the prohormone convertase enzymes PC1 and PC2 involved in its processing into ␥-MSH in the neurointermediate (NIL) of rat pituitary but not the anterior lobe (AL). 9,10 We have recently observed that genetic deficiency of circulating ␥-MSH caused by disruption of the PC2 gene is accompanied by marked salt-sensitive hypertension, 11 further suggesting an important role of this peptide in sodium metabolism and blood pressure control.POMC synthesis and processing in the NIL are under tonic dopaminergic suppression through the dopamine D 2 receptor 12,13 ; the dopamine agonist bromocriptine suppresses the synthesis of POMC and the processing enzymes PC1 and PC2, whereas the dopamine receptor antagonist haloperidol does the opposite. 14, 15 We asked if dopaminergic manipulation modified in any way the action of a diet high in sodium content to stimulate the abundance of NIL ␥-MSH content and the plasma concentration of ␥-MSH, and, if so, what effect this would have on blood pressure and s...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.