ArticlePflugers Archiv : European journal of physiology2016
Adult nephron-specific MR-deficient mice develop a severe renal PHA-1 phenotype.
Article in Pflugers Archiv : European journal of physiology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 42 citations in OpenAlex.
- Clinical implications of mineralocorticoid receptor overactivation.Clinical kidney journal · 2025Review
- Recent Advances and Perspectives on the Use of Mineralocorticoid Receptor Antagonists for the Treatment of Hypertension and Chronic Kidney Disease: A Review.Biomedicines · 2024Review
- Sodium Chloride Cotransporter in Hypertension.Biomedicines · 2024Review
- Aldosterone-independent regulation of K + secretion in the distal nephron.Current opinion in nephrology and hypertension · 2024Review
- Navigating the multifaceted intricacies of the NaPhysiological reviews · 2024Review
- Klotho is highly expressed in the chief sites of regulated potassium secretion, and it is stimulated by potassium intake.Scientific reports · 2024Article
- P2Y2 receptor decreases blood pressure by inhibiting ENaC.JCI insight · 2023Article
- Aldosterone: Renal Action and Physiological Effects.Comprehensive Physiology · 2023Article
- Blood pressure effects of sodium transport along the distal nephron.Kidney international · 2022Review
- Potassium homeostasis: sensors, mediators, and targets.Pflugers Archiv : European journal of physiology · 2022Review
- Mineralocorticoid Receptor Antagonists Cause Natriuresis in the Absence of Aldosterone.Hypertension (Dallas, Tex. : 1979) · 2022Article
- Critical role of the mineralocorticoid receptor in aldosterone-dependent and aldosterone-independent regulation of ENaC in the distal nephron.American journal of physiology. Renal physiology · 2021Article
- Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine.European heart journal · 2021Review
- Effect of Angiotensin II on ENaC in the Distal Convoluted Tubule and in the Cortical Collecting Duct of Mineralocorticoid Receptor Deficient Mice.Journal of the American Heart Association · 2020Article
- Deletion of the serine protease CAP2/Tmprss4 leads to dysregulated renal water handling upon dietary potassium depletion.Scientific reports · 2019Article
- The serine-threonine kinase PIM3 is an aldosterone-regulated protein in the distal nephron.Physiological reports · 2019Article
- Salt-sensitive transcriptome of isolated kidney distal tubule cells.Physiological genomics · 2019Article
- Lack of Renal Tubular Glucocorticoid Receptor Decreases the Thiazide-Sensitive NaFrontiers in physiology · 2019Article
- Intracellular Chloride and Scaffold Protein Mo25 Cooperatively Regulate Transepithelial Ion Transport through WNK Signaling in the Malpighian Tubule.Journal of the American Society of Nephrology : JASN · 2018Article
- Emerging Targets of Diuretic Therapy.Clinical pharmacology and therapeutics · 2017Review
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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 (MR(Pax8/LC1)) using a doxycycline-inducible system. Under standard diet, MR(Pax8/LC1) mice exhibit inability to gain weight and significant weight loss compared to control mice. Interestingly, despite failure to thrive, MR(Pax8/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 MR(Pax8/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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