Potassium Modulates Electrolyte Balance and Blood Pressure through Effects on Distal Cell Voltage and Chloride

Terker, Andrew S.; Zhang, Chong; McCormick, James A.; Lazelle, Rebecca; Zhang, Chengbiao; Meermeier, Nicholas P.; Siler, Dominic A.; Park, Hae J.; Fu, Yi; Cohen, David; Weinstein, Alan M.; Wang, Wen Hui; Yang, Chao; Ellison, David H.

doi:10.1016/j.cmet.2014.12.006

Cited by 387 publications

(595 citation statements)

References 43 publications

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“…For example, Na + restriction, diuretic treatment and MR inhibition activate the renin-angiotensin system, and angiotensin II is a known potent NCC regulator [13,33]. Likewise, aldosterone-as well as furosemide administration cause hypokalemia, which may activate NCC by direct effects on DCT plasma membrane voltage, intracellular chloride concentrations, and WNK/SPAK activity [29]. Interestingly, we also observed that the two days of dietary sodium restriction lowered plasma K + levels in mice.…”

Section: Discussionmentioning

confidence: 50%

“…Nevertheless, it remains unclear whether the effects of aldosterone on NCC are mediated directly via the MR or might be secondary to changes provoked at the systemic levels. For example, hyperaldosteronism causes hypokalemia [20] which is known to profoundly affect NCC [25,29]. Moreover, it is important to note that the enzyme 11-β-hydroxysteroid-dehydrogenase type 2 (11βHSD2), protecting the MR from activation by glucocorticoids through rapid metabolization of cortisol in humans and corticosterone in rodents, is significantly expressed only in the endportion of the DCT (DCT2) and the CS [2,5,10].…”

Section: Introductionmentioning

confidence: 99%

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The mineralocorticoid receptor (MR) regulates ENaC but not NCC in mice with random MR deletion

Czogalla

Vohra

Pentón

et al. 2016

Pflugers Arch - Eur J Physiol

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Aldosterone binds to the mineralocorticoid receptor (MR) and increases renal Na+ reabsorption via up-regulation of the epithelial Na+ channel (ENaC) and the Na+-K+-ATPase in the collecting system (CS) and possibly also via the NaCl cotransporter (NCC) in the distal convoluted tubule (DCT). However, whether aldosterone directly regulates NCC via MR, or indirectly through systemic alterations remains controversial. We used mice with deletion of MR in 20% of renal tubule cells (MR/X mice), in which MR-positive (MRwt) and -negative (MRko) cells can be studied sideby-side in the same physiological context. Adult MR/X mice showed similar mRNA and protein levels of renal ion transport proteins to control mice. In MR/X mice, no differences in NCC abundance and phosphorylation was seen between MRwt and MRko cells and dietary Na+ restriction up-regulated NCC to similar extent in both groups of cells. In contrast, MRko cells in the CS did not show any detectable alpha-ENaC abundance or apical targeting of ENaC neither on control diet nor in response to dietary Na+ restriction. Furthermore, Na+-K+-ATPase expression was unaffected in MRko cells of the DCT, while it was lost in MRko cells of the CS. In conclusion, MR is crucial for ENaC and Na+-K+-ATPase regulation in the CS, but is dispensable for NCC and Na+-K+-ATPase regulation in the DCT. PAEJ-D-16-00005 -NCC regulation is MR independent 2 ACKNOWLEDGEMENTSThe authors would like to thank Günter Schütz and Stefan Berger, Burkhard Becher, Celso E. Gomez-Sanchez, and Eric Feraille for kindly providing us with the MRlox/lox mouse line, the cmv-cre mouse line, the anti-MR antibodies, and the anti-Na + -K + -ATPase antibody, respectively. The expert technical assistance by Monique Carrel and Michèle Heidemeyer is gratefully acknowledged. GRANTS DISCLOSURESThe authors declare no conflict of interest, financial or otherwise. PAEJ-D-16-00005 -NCC regulation is MR independent 3 ABSTRACTAldosterone binds to the mineralocorticoid receptor (MR) and increases renal Na + reabsorption via up-regulation of the epithelial Na + channel (ENaC) and the Na + -K + -ATPase in the collecting system (CS) and possibly also via the NaCl cotransporter (NCC) in the distal convoluted tubule (DCT). However, whether aldosterone directly regulates NCC via MR, or indirectly through systemic alterations remains controversial. We used mice with deletion of MR in ~20% of renal tubule cells (MR/X mice), in which MR-positive (MR wt ) and -negative (MR ko ) cells can be studied sideby-side in the same physiological context. Adult MR/X mice showed similar mRNA and protein levels of renal ion transport proteins to control mice. In MR/X mice, no differences in NCC abundance and phosphorylation was seen between MR wt and MR ko cells and dietary Na + restriction up-regulated NCC to similar extent in both groups of cells. In contrast, MR ko cells in the CS did not show any detectable alphaENaC abundance or apical targeting of ENaC neither on control diet nor in response to dietary Na + restriction. Furtherm...

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Section: Discussionmentioning

confidence: 50%

Section: Introductionmentioning

confidence: 99%

The mineralocorticoid receptor (MR) regulates ENaC but not NCC in mice with random MR deletion

Czogalla

Vohra

Pentón

et al. 2016

Pflugers Arch - Eur J Physiol

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“…The localization of the mineralocorticoid receptor in the ASDN and other renal cell types 16 and/or a largely aldosteroneindependent ENaC function in the DCT2/ CNT 17 may contribute to the complexity of corticosteroid effects on ASDN function. A cross-talk between the angiotensin II membrane receptor and the mineralocorticoid receptor signaling pathways is well established, which was shown by Shibata et al 18 and Terker et al 19 Conditional inactivation of the mineralocorticoid receptor in the CD and late CNT is only compensated under standard diet but not when sodium supply is limited. 20 The phenotype is, thus, comparable with that of late CNT/CD-specific ENaC knockout, where the same AQP2-Cre transgenic line was used.…”

Section: Rescue Of Sodium and Potassiummentioning

confidence: 88%

Severe Salt–Losing Syndrome and Hyperkalemia Induced by Adult Nephron–Specific Knockout of the Epithelial Sodium Channel α-Subunit

Perrier

Boscardin

Malsure

et al. 2015

JASN

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Systemic pseudohypoaldosteronism type 1 (PHA-1) is a severe salt-losing syndrome caused by loss-of-function mutations of the amiloride-sensitive epithelial sodium channel (ENaC) and characterized by neonatal lifethreatening hypovolemia and hyperkalemia. The very high plasma aldosterone levels detected under hypovolemic or hyperkalemic challenge can lead to increased or decreased sodium reabsorption, respectively, through the Na + /Cl 2 cotransporter (NCC). However, the role of ENaC deficiency remains incompletely defined, because constitutive inactivation of individual ENaC subunits is neonatally lethal in mice. We generated adult inducible nephron-specific aENaC-knockout mice (Scnn1a) that exhibit hyperkalemia and body weight loss when kept on a regular-salt diet, thus mimicking PHA-1. Compared with control mice fed a regular-salt diet, knockout mice fed a regular-salt diet exhibited downregulated expression and phosphorylation of NCC protein, despite high plasma aldosterone levels. In knockout mice fed a high-sodium and reduced-potassium diet (rescue diet), although plasma aldosterone levels remained significantly increased, NCC expression returned to control levels, and body weight, plasma and urinary electrolyte concentrations, and excretion normalized. Finally, shift to a regular diet after the rescue diet reinstated the symptoms of severe PHA-1 syndrome and significantly reduced NCC phosphorylation. In conclusion, lack of ENaC-mediated sodium transport along the nephron cannot be compensated for by other sodium channels and/or transporters, only by a high-sodium and reduced-potassium diet. We further conclude that hyperkalemia becomes the determining factor in regulating NCC activity, regardless of sodium loss, in the ENaC-mediated salt-losing PHA-1 phenotype.

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“…Other stimuli for aldosterone secretion, such as hyperkalemia, may selectively upregulate KS-WNK1 protein expression via additional undefined mechanisms to attenuate L-WNK1 and NCC activity (55,59,60). Such effects may act in concert with changes in intracellular [Cl-] to suppress WNK activity (61). Additionally, other SGK1-dependent effects on NCC, including suppression of WNK4-mediated NCC degradation (46) or ubiquitylation of NCC by NEDD4-2 (35), are not shown here to highlight the mechanism of SPAK/OSR1 activation described in this study.…”

Section: Discussionmentioning

confidence: 99%

Alternatively spliced proline-rich cassettes link WNK1 to aldosterone action

Roy

Al‐Qusairi

Donnelly

et al. 2015

Journal of Clinical Investigation

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Potassium Modulates Electrolyte Balance and Blood Pressure through Effects on Distal Cell Voltage and Chloride

Cited by 387 publications

References 43 publications

The mineralocorticoid receptor (MR) regulates ENaC but not NCC in mice with random MR deletion

The mineralocorticoid receptor (MR) regulates ENaC but not NCC in mice with random MR deletion

Severe Salt–Losing Syndrome and Hyperkalemia Induced by Adult Nephron–Specific Knockout of the Epithelial Sodium Channel α-Subunit

Alternatively spliced proline-rich cassettes link WNK1 to aldosterone action

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