Mechanisms of Renal Control of Potassium Homeostasis in Complete Aldosterone Deficiency

Todkar, Abhijeet P.; Picard, Nicolas; Loffing‐Cueni, Dominique; Sørensen, Mads Vaarby; Mihailova, Marija; Nesterov, Viatcheslav; Makhanova, Natalia; Korbmacher, Christoph; Wagner, Carsten A.; Loffing, Johannes

doi:10.1681/asn.2013111156

Cited by 71 publications

(72 citation statements)

References 61 publications

(100 reference statements)

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“…Under control conditions, the MR ko cells in the CS did not show any detectable αENaC expression or apical localization of ENaC. Dietary Na + restriction failed to up-regulate αENaC and to translocate the channel to the cell surface in MR ko cells, which is consistent with the results of many previous studies including those analyzing mouse models with a constitutive or an inducible inactivation of the MR in the CNT and CD [2,21,31]. Interestingly, although the loss of the MR did not interfere with the abundance of the Na + -K + -ATPase in the DCT, it did in the CS of the MR/X mice.…”

Section: Discussionsupporting

confidence: 90%

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: Discussionsupporting

confidence: 90%

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

Self Cite

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“…The sodium chloride cotransporter was downregulated to promote distal sodium delivery, and both ENaC and ROMK were upregulated. Interestingly, angiotensin signaling appeared to play a permissive role for potassium secretion, since treatment with losartan rendered the mice unable to handle moderate dietary potassium [88]. This is consistent with clinical data showing that dual RAAS blockade raises serum potassium more than single RAAS blockade [89, 78].…”

Section: Potassium: Foe – Deleterious Effects Of Potassium Excessmentioning

confidence: 52%

Potassium: friend or foe?

Rodan

2016

Pediatr Nephrol

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The kidney plays an essential role in maintaining homeostasis of blood ion concentrations. Because the concentration gradient of potassium across the cell membrane is a key determinant of the membrane potential of cells, even small deviations in serum potassium from the normal setpoint can lead to severe muscle dysfunction, resulting in respiratory failure and cardiac arrest. Less severe hypo- and hyperkalemia are also associated with morbidity and mortality across various patient populations. In addition, deficiencies in potassium intake have been associated with hypertension and adverse cardiovascular and renal outcomes. This is likely due in part to the interrelated handling of sodium and potassium by the kidney. Here, data on the beneficial effects of potassium on blood pressure and cardiovascular and renal outcomes will be reviewed, along with the physiological basis for these effects. In some patient populations, however, potassium excess is deleterious. Risk factors for the development of hyperkalemia will be reviewed, as well as the risks and benefits of existing and emerging therapies for hyperkalemia.

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“…The results showed that renal adaptation to a physiological K (+) load in aldosterone deficiency is possible by means of aldosterone-independent activation of the renal outer medullary K (+) channel and epithelial sodium channel. Angiotensin II may also contribute to this (7). …”

Section: Discussionmentioning

confidence: 99%

Corticosterone Methyl Oxidase Deficiency Type 1 with Normokalemia in an Infant

Üstyol¹,

Atabek²,

Taylor³

et al. 2016

Jcrpe

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Isolated aldosterone synthase deficiency may result in life-threatening salt-wasting and failure to thrive. The condition involves hyperkalemia accompanying hyponatremia. Two types of aldosterone synthase deficiency may be observed depending on hormone levels: corticosterone methyl oxidase type 1 (CMO 1) and CMO 2. Herein, we describe a Turkish infant patient with aldosterone synthase deficiency who presented with failure to thrive and salt wasting but with normal potassium levels. Urinary steroid characteristics were compatible with CMO I deficiency. Diagnosis of aldosterone synthase deficiency was confirmed by mutational analysis of the CYP11B2 gene which identified the patient as homozygous for two mutations: c.788T>A (p.Ile263Asn) and c.1157T>C (p.Val386Ala). Family genetic study revealed that the mother was heterozygous for c.788T>A and homozygous for c.1157T>C and the father was heterozygous for both c.788T>A and c.1157T>C. To the best of our knowledge, this is only the second Turkish case with a confirmed molecular basis of type 1 aldosterone synthase deficiency. This case is also significant in showing that spot urinary steroid analysis can assist with the diagnosis and that hyperkalemia is not necessarily part of the disease.

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Mechanisms of Renal Control of Potassium Homeostasis in Complete Aldosterone Deficiency

Cited by 71 publications

References 61 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

Potassium: friend or foe?

Corticosterone Methyl Oxidase Deficiency Type 1 with Normokalemia in an Infant

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