Adult nephron-specific MR-deficient mice develop a severe renal PHA-1 phenotype

Canonica, Jérémie; Sergi, Chloé; Klusoňová, Petra; Odermatt, Alex; Koesters, Robert; Loffing‐Cueni, Dominique; Loffing, Johannes; Rossier, Bernard C.; Frateschi, Simona; Hummler, Edith

doi:10.1007/s00424-015-1785-2

Cited by 36 publications

(41 citation statements)

References 33 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: 93%

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: 93%

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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“…Inducible kidney tubule‐specific MR KO (tubular MR KO) mice display a severe pseudohypoaldosteronism type 1 phenotype characterized by weight loss, increased urinary Na + excretion, hyponatremia, hyperkalemia, and high plasma aldosterone levels . This phenotype is attributed to decreased Na + reabsorption and K + secretion along the ASDN.…”

Section: Resultsmentioning

confidence: 99%

“…The previously described doxycycline‐inducible kidney tubule‐specific and mosaic MR‐deficient mice were used for experiments. Kidney tubule‐specific MR knockout (KO) induced by administration of doxycycline hydrochloride (2 mg/mL in drinking water) for 15 days to 4‐week‐old mice.…”

Section: Methodsmentioning

confidence: 99%

“…Inducible kidney tubule-specific MR KO (tubular MR KO) mice display a severe pseudohypoaldosteronism type 1 phenotype characterized by weight loss, increased urinary Na + excretion, hyponatremia, hyperkalemia, and high plasma aldosterone levels. 20 This phenotype is attributed to decreased Na + reabsorption and K + secretion along the ASDN. To investigate whether MR directly or indirectly controls primary cilium length, we measured the length of cilia along the ASDN in tubular MR KO mice and wild-type (WT) control littermates.…”

Section: A Cell Autonomous Mechanism Controls the Length Of Primarymentioning

confidence: 99%

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Aldosterone controls primary cilium length and cell size in renal collecting duct principal cells

et al. 2019

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This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. AbstractPrimary cilia are nonmotile sensory organelles found on the surface of almost all kidney tubule epithelial cells. Being exposed to the tubular lumen, primary cilia are thought to be chemo-and mechanosensors of luminal composition and flux, respectively. We hypothesized that, Na + transport and primary cilia exist in a sensory functional connection in mature renal tubule epithelial cells. Our results demonstrate that primary cilium length is reduced in mineralocorticoid receptor (MR) knockout (KO) mice in a cell autonomous manner along the aldosterone-sensitive distal nephron (ADSN) compared with wild type (as µm ± SEM; 3.1 ± 0.2 vs 4.0 ± 0.1). In mouse cortical collecting duct (mCCD) cl1 cells, which are a model of collecting duct (CD) principal cells, changes in Na + transport intensity were found to mediate primary cilium length in response to aldosterone (as µm ± SEM: control: 2.7 ± 0.9 vs aldosterone treated: 3.8 ± 0.8). Cilium length was positively correlated with the availability of IFT88, a major intraflagellar anterograde transport complex B component, which is stabilized in response to exposure to aldosterone treatment. This suggests that the abundance of IFT88 is a regulated, rate limiting factor in the elongation of primary cilia. As previously observed in vivo, aldosterone treatment increased cell volume of cultured CD principal cells. Knockdown of IFT88 prevents ciliogenesis and inhibits the adaptive increase in cell size that was observed in response to aldosterone treatment. In conclusion, our results reveal a functional connection between Na + transport, primary cilia, and cell size, which may play a key role in the morphological and functional adaptation of the CD to sustained changes in active Na + reabsorption due to variations in aldosterone secretion. K E Y W O R D Saldosterone, cell volume, collecting duct, primary cilium, sodium 2626 | KOMARYNETS ET Al.

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“…When challenged with a low sodium diet, however, the mice had increased sodium and water excretion and loss of body weight. Two more recent independent studies have deleted the MR along the mouse adult nephron via a tamoxifeninducible Pax 8-Cre recombinase transgene from four weeks (Canonica et al 2016) and eight weeks (Terker et al 2016) of age. In contrast to the MR AQP2Cre mutant mice, adult MR Pax 8-Cre mice in both studies showed features of severe PHA-1 on a normal sodium diet, significant weight loss, high urinary sodium excretion, hyperkalaemia and elevated plasma aldosterone.…”

Section: Epithelial Cell-specific Deletion Of the Mr Genementioning

confidence: 99%

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor null mice: informing cell-type-specific roles

Cole

Young

2017

Journal of Endocrinology

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The mineralocorticoid receptor (MR) mediates the actions of two important adrenal corticosteroid hormones, aldosterone and cortisol. The cell signalling roles of the MR in vivo have expanded enormously since the cloning of human MR gene 30 years ago and the first MR gene knockout in mice nearly 20 years ago. Complete ablation of the MR revealed important roles postnatally for regulation of kidney epithelial functions, with MR-null mice dying 1-2 weeks postnatally from renal salt wasting and hyperkalaemia, with elevated plasma renin and aldosterone. Generation of tissue-selective MR-deficient mice using Cre recombinase-LoxP gene targeting has made it possible to analyse mice lacking MR only in specific cell types. Targeting renal-specific MR has differentiated roles in specific compartments of the kidney. Ablating MR in neurons of the forebrain reinforced important roles of the MR in response to stress, behaviour and anxiety, but suggested a minimal role in maintaining basal HPA axis tone. Deletion of the MR in macrophages and other cell types of the cardiovascular system clearly defined important roles for the regulation of cardiovascular physiology and pathophysiology. Knockdown of MR mRNA in vivo using antisense/siRNA approaches, and similarly MR overexpression, has provided useful rodent models to study physiological roles of MR signalling in vivo. More recently, targeted mutation of specific domains of the MR such as the DBD has defined genomic vs non-genomic roles in vivo. New tissue-selective MR-null models are required to define roles of MR signalling in other regions of the brain, the eye, gastrointestinal tract, lung, skin, breast and gonadal organs.

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Adult nephron-specific MR-deficient mice develop a severe renal PHA-1 phenotype

Cited by 36 publications

References 33 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

Aldosterone controls primary cilium length and cell size in renal collecting duct principal cells

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor null mice: informing cell-type-specific roles

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