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Control of sodium and potassium homeostasis by renal distal convoluted tubules
Distal convoluted tubules (DCT), which contain the Na-Cl cotransporter (NCC) inhibited by thiazide diuretics, undergo complex modulation to preserve Na(+) and K(+) homeostasis. The lysine kinases 1 and 4 (WNK1 and WNK4), identified as hyperactive in the hereditary disease pseudohypoaldosteronism typ...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Associação Brasileira de Divulgação Científica
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9925193/ https://www.ncbi.nlm.nih.gov/pubmed/36790288 http://dx.doi.org/10.1590/1414-431X2023e12392 |
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author | Gallafassi, E.A. Bezerra, M.B. Rebouças, N.A. |
author_facet | Gallafassi, E.A. Bezerra, M.B. Rebouças, N.A. |
author_sort | Gallafassi, E.A. |
collection | PubMed |
description | Distal convoluted tubules (DCT), which contain the Na-Cl cotransporter (NCC) inhibited by thiazide diuretics, undergo complex modulation to preserve Na(+) and K(+) homeostasis. The lysine kinases 1 and 4 (WNK1 and WNK4), identified as hyperactive in the hereditary disease pseudohypoaldosteronism type 2, are responsible for activation of NCC and consequent hypokalemia and hypertension. WNK4, highly expressed in DCT, activates the SPAK/OSR1 kinases, which phosphorylate NCC and other regulatory proteins and transporters in the distal nephron. WNK4 works as a chloride sensor through a Cl(-) binding site, which acts as an on/off switch at this kinase in response to changes of basolateral membrane electrical potential, the driving force of cellular Cl(-) efflux. High intracellular Cl(-) in hyperkalemia decreases NCC phosphorylation and low intracellular Cl(-) in hypokalemia increases NCC phosphorylation and activity, which makes plasma K(+) concentration a central modulator of NCC and of K(+) secretion. The WNK4 phosphorylation by cSrc or SGK1, activated by angiotensin II or aldosterone, respectively, is another relevant mechanism of NCC, ENaC, and ROMK modulation in states such as volume reduction, hyperkalemia, and hypokalemia. Loss of NCC function induces upregulation of electroneutral NaCl reabsorption by type B intercalated cells through the combined activity of pendrin and NDCBE, as demonstrated in double knockout mice (KO) animal models, Ncc/pendrin or Ncc/NDCBE. The analysis of ks-Nedd-4-2 KO animal models introduced the modulation of NEDD4-2 by intracellular Mg(2+) activity as an important regulator of NCC, explaining the thiazide-induced persistent hypokalemia. |
format | Online Article Text |
id | pubmed-9925193 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Associação Brasileira de Divulgação Científica |
record_format | MEDLINE/PubMed |
spelling | pubmed-99251932023-02-14 Control of sodium and potassium homeostasis by renal distal convoluted tubules Gallafassi, E.A. Bezerra, M.B. Rebouças, N.A. Braz J Med Biol Res Review Distal convoluted tubules (DCT), which contain the Na-Cl cotransporter (NCC) inhibited by thiazide diuretics, undergo complex modulation to preserve Na(+) and K(+) homeostasis. The lysine kinases 1 and 4 (WNK1 and WNK4), identified as hyperactive in the hereditary disease pseudohypoaldosteronism type 2, are responsible for activation of NCC and consequent hypokalemia and hypertension. WNK4, highly expressed in DCT, activates the SPAK/OSR1 kinases, which phosphorylate NCC and other regulatory proteins and transporters in the distal nephron. WNK4 works as a chloride sensor through a Cl(-) binding site, which acts as an on/off switch at this kinase in response to changes of basolateral membrane electrical potential, the driving force of cellular Cl(-) efflux. High intracellular Cl(-) in hyperkalemia decreases NCC phosphorylation and low intracellular Cl(-) in hypokalemia increases NCC phosphorylation and activity, which makes plasma K(+) concentration a central modulator of NCC and of K(+) secretion. The WNK4 phosphorylation by cSrc or SGK1, activated by angiotensin II or aldosterone, respectively, is another relevant mechanism of NCC, ENaC, and ROMK modulation in states such as volume reduction, hyperkalemia, and hypokalemia. Loss of NCC function induces upregulation of electroneutral NaCl reabsorption by type B intercalated cells through the combined activity of pendrin and NDCBE, as demonstrated in double knockout mice (KO) animal models, Ncc/pendrin or Ncc/NDCBE. The analysis of ks-Nedd-4-2 KO animal models introduced the modulation of NEDD4-2 by intracellular Mg(2+) activity as an important regulator of NCC, explaining the thiazide-induced persistent hypokalemia. Associação Brasileira de Divulgação Científica 2023-02-10 /pmc/articles/PMC9925193/ /pubmed/36790288 http://dx.doi.org/10.1590/1414-431X2023e12392 Text en https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Review Gallafassi, E.A. Bezerra, M.B. Rebouças, N.A. Control of sodium and potassium homeostasis by renal distal convoluted tubules |
title | Control of sodium and potassium homeostasis by renal distal convoluted tubules |
title_full | Control of sodium and potassium homeostasis by renal distal convoluted tubules |
title_fullStr | Control of sodium and potassium homeostasis by renal distal convoluted tubules |
title_full_unstemmed | Control of sodium and potassium homeostasis by renal distal convoluted tubules |
title_short | Control of sodium and potassium homeostasis by renal distal convoluted tubules |
title_sort | control of sodium and potassium homeostasis by renal distal convoluted tubules |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9925193/ https://www.ncbi.nlm.nih.gov/pubmed/36790288 http://dx.doi.org/10.1590/1414-431X2023e12392 |
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