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

  • Molecular and cellular mechanisms of disease
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Abstract

Aldosterone is the main mineralocorticoid hormone controlling sodium balance, fluid homeostasis, and blood pressure by regulating sodium reabsorption in the aldosterone-sensitive distal nephron (ASDN). Germline loss-of-function mutations of the mineralocorticoid receptor (MR) in humans and in mice lead to the “renal” form of type 1 pseudohypoaldosteronism (PHA-1), a case of aldosterone resistance characterized by salt wasting, dehydration, failure to thrive, hyperkalemia, and metabolic acidosis. To investigate the importance of MR in adult epithelial cells, we generated nephron-specific MR knockout mice (MRPax8/LC1) using a doxycycline-inducible system. Under standard diet, MRPax8/LC1 mice exhibit inability to gain weight and significant weight loss compared to control mice. Interestingly, despite failure to thrive, MRPax8/LC1 mice survive but develop a severe PHA-1 phenotype with higher urinary Na+ levels, decreased plasma Na+, hyperkalemia, and higher levels of plasma aldosterone. This phenotype further worsens and becomes lethal under a sodium-deficient diet. Na+/Cl− co-transporter (NCC) protein expression and its phosphorylated form are downregulated in the MRPax8/LC1 knockouts, as well as the αENaC protein expression level, whereas the expression of glucocorticoid receptor (GR) is increased. A diet rich in Na+ and low in K+ does not restore plasma aldosterone to control levels but is sufficient to restore body weight, plasma, and urinary electrolytes. In conclusion, MR deletion along the nephron fully recapitulates the features of severe human PHA‐1. ENaC protein expression is dependent on MR activity. Suppression of NCC under hyperkalemia predominates in a hypovolemic state.

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Abbreviations

ASDN:

Aldosterone-sensitive distal nephron

MR:

Mineralocorticoid receptor

GR:

Glucocorticoid receptor

ENaC:

Epithelial sodium channel

NCC:

Na+/Cl− co-transporter

AQP2:

Aquaporin 2

Hsd11b2:

11β-Hydroxysteroid dehydrogenase type 2

PHA-1:

Type 1 pseudohypoaldosteronism

RAAS:

Renin-angiotensin-aldosterone system

PCT:

Proximal convoluted tubule

PST:

Proximal straight tubule

TAL:

Thick ascending limb

DCT:

Distal convoluted tubule

CNT:

Connecting tubule

CCD:

Cortical collecting duct

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Acknowledgments

The authors would like to thank Günter Schütz and Stefan Berger for kindly providing us with the Nr3c2lox/lox mouse line and Celso E. Gomez-Sanchez for the antibody against MR. We also like to thank Denise Kratschmar for LC-MS steroid measurements and Anne-Marie Mérillat for figure editing. Moreover, the authors would like to thank all of the members of the laboratory of Edith Hummler for helpful and interactive discussions. Finally, the authors would like to acknowledge the contribution of the COST Action ADMIRE BM1301.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, University of Lausanne, Rue du Bugnon 27, CH-1011, Lausanne, Switzerland

    Jérémie Canonica, Chloé Sergi, Bernard Rossier, Simona Frateschi & Edith Hummler

  2. National Center of Competence in Research “Kidney.CH”, Lausanne, Switzerland

    Jérémie Canonica, Petra Klusonova, Alex Odermatt, Dominique Loffing-Cueni, Johannes Loffing, Bernard Rossier, Simona Frateschi & Edith Hummler

  3. Service of Nephrology Department, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

    Marc Maillard

  4. Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland

    Petra Klusonova & Alex Odermatt

  5. Hôpital Tenon, Université Pierre et Marie Curie, Paris, France

    Robert Koesters

  6. Institute of Anatomy, University of Zurich, Zurich, Switzerland

    Dominique Loffing-Cueni & Johannes Loffing

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  1. Jérémie Canonica
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  11. Edith Hummler
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Corresponding author

Correspondence to Edith Hummler.

Ethics declarations

Animal maintenance and all experimental procedures in mice were in accordance with the Swiss federal guidelines and were approved by the veterinarian local authorities (“Service de la consommation et des affaires vétérinaires”) of the Canton de Vaud, Switzerland.

Conflict of interest

The authors declare that they have no competing interests.

Funding

This work was supported by the Swiss National Center of Competence in Research (NCCR Kidney CH) and the Swiss National Science Foundation (grants SNF 31003A_144198/1 and 31003A_163347/1 to Edith Hummler, 31003A_159454 to Alex Odermatt and 310030_143929 to Johannes Loffing).

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Canonica, J., Sergi, C., Maillard, M. et al. Adult nephron-specific MR-deficient mice develop a severe renal PHA-1 phenotype. Pflugers Arch - Eur J Physiol 468, 895–908 (2016). https://doi.org/10.1007/s00424-015-1785-2

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