Direct and Indirect Mineralocorticoid Effects Determine Distal Salt Transport

Terker, Andrew S.; Yarbrough, Bethzaida; Ferdaus, Mohammed Z.; Lazelle, Rebecca; Erspamer, Kayla J.; Meermeier, Nicholas P.; Park, Hae J.; McCormick, James A.; Yang, Chao; Ellison, David H.

doi:10.1681/asn.2015070815

Cited by 121 publications

(127 citation statements)

References 46 publications

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“…Interestingly, we also observed that the two days of dietary sodium restriction lowered plasma K + levels in mice. Consistent with a dominant role of plasma K + , two groups were just able to show that the down-regulation of NCC in mice with kidney-specific MR deletion could be overcome or at least mitigated by employing dietary K + restriction to normalize plasma K + [6,28]. Likewise, recent studies using mice deficient for 11βHSD2 by Hunter and colleagues challenged the conventional concept of mineralocorticoid signaling in the DCT [10].…”

Section: Discussionmentioning

confidence: 92%

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: 92%

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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“…In the kidney, the disease familial hyperkalemic hypertension (FHHt) exemplifies how studying such genes can lead to the elucidation of novel regulatory pathways. The discovery that mutations in the With-no-lysine [K] kinases (WNKs) Wnk1 and Wnk4 cause FHHt (1,2) and, more recently, that mutations in Cullin 3 (Cul3) (OMIM 614496, PHA2E) (3)(4)(5) and Kelch-like 3 (Klhl3) (4, 5) -components of an E3 ubiquitin ligase complex -also cause the disease has revealed a canonical pathway for the regulation of the Na + Cl -cotransporter (NCC). Along the distal convoluted tubule (DCT), NCC is activated by phosphorylation at several amino-terminal residues (6,7).…”

Section: Introductionmentioning

confidence: 99%

Mutant Cullin 3 causes familial hyperkalemic hypertension via dominant effects

Ferdaus¹,

Miller²,

Agbor³

et al. 2017

JCI Insight

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“…However, aldosterone administration increases urinary K ϩ loss, which, in turn, will reduce serum K ϩ levels and, thus, stimulate NCC activity. A recent study in mice in which the mineralocorticoid receptor was eliminated exclusively along the entire nephron strongly suggested that the aldosterone modulation of NCC is an indirect, rather than, direct effect of the changes in serum K ϩ (133). Furthermore, 11␤-hydroxysteroid dehydrogenase type 2 is not present in DCT1, and it is not clear whether it is expressed in DCT2 cells (reviewed in Ref.…”

Section: F137 Slc12 Cotransporters In the Kidneymentioning

confidence: 99%

Physiological role of SLC12 family members in the kidney

Bazúa‐Valenti

Castañeda‐Bueno

Gamba

2016

American Journal of Physiology-Renal Physiology

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The solute carrier family 12, as numbered according to Human Genome Organisation (HUGO) nomenclature, encodes the electroneutral cation-coupled chloride cotransporters that are expressed in many cells and tissues; they play key roles in important physiological events, such as cell volume regulation, modulation of the intracellular chloride concentration, and transepithelial ion transport. Most of these family members are expressed in specific regions of the nephron. The Na-K-2Cl cotransporter NKCC2, which is located in the thick ascending limb, and the Na-Cl cotransporter, which is located in the distal convoluted tubule, play important roles in salt reabsorption and serve as the receptors for loop and thiazide diuretics, respectively (Thiazide diuretics are among the most commonly prescribed drugs in the world.). The activity of these transporters correlates with blood pressure levels; thus, their regulation has been a subject of intense research for more than a decade. The K-Cl cotransporters KCC1, KCC3, and KCC4 are expressed in several nephron segments, and their role in renal physiology is less understood but nevertheless important. Evidence suggests that they are involved in modulating proximal tubule glucose reabsorption, thick ascending limb salt reabsorption and collecting duct proton secretion. In this work, we present an overview of the physiological roles of these transporters in the kidney, with particular emphasis on the knowledge gained in the past few years.

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Direct and Indirect Mineralocorticoid Effects Determine Distal Salt Transport

Cited by 121 publications

References 46 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

Mutant Cullin 3 causes familial hyperkalemic hypertension via dominant effects

Physiological role of SLC12 family members in the kidney

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