0
views
0
recommends
+1 Recommend
1 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found

      Mineralocorticoid-Induced Sodium Appetite and Renal Salt Retention: Evidence for Common Signaling and Effector Mechanisms

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          An increase in renal sodium chloride (salt) retention and an increase in sodium appetite are the body's responses to salt restriction or depletion in order to restore salt balance. Renal salt retention and increased sodium appetite can also be maladaptive and sustain the pathophysiology in conditions like salt-sensitive hypertension and chronic heart failure. Here we review the central role of the mineralocorticoid aldosterone in both the increase in renal salt reabsorption and sodium appetite. We discuss the working hypothesis that aldosterone activates similar signaling and effector mechanisms in the kidney and brain, including the mineralocorticoid receptor, the serum- and glucocorticoid-induced kinase SGK1, the ubiquitin ligase NEDD4-2, and the epithelial sodium channel ENaC. The latter also mediates the gustatory salt sensing in the tongue, which is required for the manifestation of increased salt intake. Effects of aldosterone on both the brain and kidney synergize with the effects of angiotensin II. Thus, mineralocorticoids appear to induce similar molecular pathways in the kidney, brain, and possibly tongue, which could provide opportunities for more effective therapeutic interventions. Inhibition of renal salt reabsorption is compensated by stimulation of salt appetite and vice versa; targeting both mechanisms should be more effective. Inhibiting the arousal to consume salty food may improve a patient's compliance to reducing salt intake. While a better understanding of the molecular mechanisms is needed and will provide new therapeutic options, current pharmacological interventions that target both salt retention and sodium appetite include mineralocorticoid receptor antagonists and potentially inhibitors of angiotensin II and ENaC.

          Related collections

          Most cited references 72

          • Record: found
          • Abstract: found
          • Article: not found

          The cells and peripheral representation of sodium taste in mice

          Salt taste in mammals can trigger two divergent behavioural responses. In general, concentrated saline solutions elicit robust behavioural aversion, while low concentrations of NaCl are typically attractive, particularly after sodium depletion1-5. Notably, the attractive salt pathway is selectively responsive to sodium and inhibited by amiloride, while the aversive one functions as a non-selective detector for a wide range of salts1-3, 6-9. Since amiloride is a potent inhibitor of the epithelial sodium channel (ENaC), ENaC has been proposed to function as a component of the salt taste receptor system1, 3, 6-14. Here, we examine the basis of sodium sensing in the mammalian taste system. Previously, we showed that four of the five basic taste qualities, sweet, sour, bitter and umami are mediated by separate taste receptor cells (TRC) each tuned to a single taste modality, and wired to elicit stereotypical behavioural responses5, 15-18. We now demonstrate that sodium sensing is also mediated by a dedicated population of TRCs. These taste cells express the epithelial sodium channel ENaC19, 20, and mediate behavioural attraction to NaCl. We genetically engineered mice lacking ENaCα in TRCs, and produced animals exhibiting a complete loss of salt attraction and sodium taste responses. Together, these studies substantiate independent cellular substrates for all five basic taste qualities, and validate the essential role of ENaC for sodium taste in mice.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Significance of SGK1 in the regulation of neuronal function.

            The present brief review highlights the putative role of the serum- and glucocorticoid-inducible-kinase-1 (SGK1) in the regulation of neuronal function. SGK1 is genomically upregulated by cell shrinkage and by a variety of hormones including mineralocorticoids and glucocorticoids. The kinase is activated by insulin and growth factors via phosphatidylinositide-3-kinase (PI3-kinase), phosphoinositide-dependent kinase PDK1 and mammalian target of rapamycin mTORC2. SGK1 upregulates ion channels (e.g. SCN5A, ENaC, ASIC1, TRPV5,6, ROMK, Kv1.1-5, KCNEx/KCNQ1-5, GluR6, VSOAC, ClC2, CFTR), carriers (e.g. NHE3, NKCC2, NCC, NaPiIIb, SMIT, GLUT1,4, SGLT1, NaDC, EAAT1-5, SN1, ASCT2, 4F2/LAT, PepT2), and the Na(+)/K(+)-ATPase. SGK1 regulates enzymes (e.g. glycogen-synthase-kinase-3, ubiquitin-ligase Nedd4-2, phosphomannose-mutase-2), and transcription factors (e.g. forkhead transcription factor Foxo3a, β-catenin, nuclear factor-kappa-B (NFB)). SGK1 participates in the regulation of transport, hormone release, neuroexcitability, inflammation, coagulation, cell proliferation and apoptosis. SGK1 contributes to regulation of renal Na(+) retention, renal K(+) elimination, salt appetite, gastric acid secretion, intestinal Na(+)/H(+) exchange and nutrient transport, insulin-dependent salt sensitivity of blood pressure, salt sensitivity of peripheral glucose uptake, cardiac repolarization and memory consolidation. Presumably, SGK1 contributes to the regulation of diverse cerebral functions (e.g. memory consolidation, fear retention) and the pathophysiology of several cerebral diseases (e.g. Parkinson's disease, schizophrenia, depression, Alzheimer's disease). Despite multiple SGK1 functions, the phenotype of the SGK1 knockout mouse is mild and becomes only apparent under challenging conditions.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Expression and phosphorylation of the Na+-Cl- cotransporter NCC in vivo is regulated by dietary salt, potassium, and SGK1.

              The Na-Cl cotransporter NCC is expressed in the distal convoluted tubule, activated by phosphorylation, and has been implicated in renal NaCl and K(+) homeostasis. The serum and glucocorticoid inducible kinase 1 (SGK1) contributes to renal NaCl retention and K(+) excretion, at least in part, by stimulating the epithelial Na(+) channel and Na(+)-K(+)-ATPase in the downstream segments of aldosterone-sensitive Na(+)/K(+) exchange. In this study we confirmed in wild-type mice (WT) that dietary NaCl restriction increases renal NCC expression and its phosphorylation at Thr(53), Thr(58), and Ser(71), respectively. This response, however, was attenuated in mice lacking SGK1 (Sgk1(-/-)), which may contribute to impaired NaCl retention in those mice. Total renal NCC expression and phosphorylation at Thr(53), Thr(58), and Ser(71) in WT were greater under low- compared with high-K(+) diet. This finding is consistent with a regulation of NCC to modulate Na(+) delivery to downstream segments of Na(+)/K(+) exchange, thereby modulating K(+) excretion. Dietary K(+)-dependent variation in renal expression of total NCC and phosphorylated NCC were not attenuated in Sgk1(-/-) mice. In fact, high-K(+) diet-induced NCC suppression was enhanced in Sgk1(-/-) mice. The hyperkalemia induced in Sgk1(-/-) mice by a high-K(+) diet may have augmented NCC suppression, thereby increasing Na(+) delivery and facilitating K(+) excretion in downstream segments of impaired Na(+)/K(+) exchange. In summary, changes in NaCl and K(+) intake altered NCC expression and phosphorylation, an observation consistent with a role of NCC in NaCl and K(+) homeostasis. The two maneuvers dissociated plasma aldosterone levels from NCC expression and phosphorylation, implicating additional regulators. Regulation of NCC expression and phosphorylation by dietary NaCl restriction appears to involve SGK1.
                Bookmark

                Author and article information

                Journal
                NEP
                Nephron Physiol
                10.1159/issn.1660-2137
                Nephron Physiology
                S. Karger AG
                1660-2137
                2014
                December 2014
                06 November 2014
                : 128
                : 1-2
                : 8-16
                Affiliations
                Departments of aMedicine and bPharmacology, University of California San Diego, La Jolla, Calif., and cDepartment of Veterans Affairs, San Diego Healthcare System, San Diego, Calif., USA
                Author notes
                *Dr. Volker Vallon, Division of Nephrology and Hypertension, Departments of Medicine and Pharmacology, University of California San Diego and VA San Diego Healthcare System, 3350 La Jolla Village Drive (9151), San Diego, CA 92161 (USA), E-Mail vvallon@ucsd.edu
                Article
                368264 PMC4275376 Nephron Physiol 2014;128:8-16
                10.1159/000368264
                PMC4275376
                25376899
                © 2014 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 1, Pages: 9
                Categories
                Review

                Comments

                Comment on this article