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New functions and roles of the Na+-H+-exchanger NHE3

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Abstract

The sodium/proton exchanger isoform 3 (NHE3) is expressed in the intestine and the kidney, where it contributes to hydrogen secretion and sodium (re)absorption. The roles of this transporter have been studied by the use of the respective knockout mice and by using pharmacological inhibitors. Whole-body NHE3 knockout mice suffer from a high mortality rate (with only ∼30% of mice surviving into adulthood), and based on the expression of NHE3 in both intestine and kidney, some conclusions that were originally derived were based on this rather complex phenotype. In the last decade, more refined models have been developed that added temporal and spatial control of NHE3 expression. For example, novel mouse models have been developed with a knockout of NHE3 in intestinal epithelial cells, tubule/collecting duct of the kidney, proximal tubule of the kidney, and thick ascending limb of the kidney. These refined models have significantly contributed to our understanding of the role of NHE3 in a tissue/cell type-specific manner. In addition, tenapanor was developed, which is a non-absorbable, intestine-specific NHE3 inhibitor. In rat and human studies, tenapanor lowered intestinal Pi uptake and was effective in lowering plasma Pi levels in patients on hemodialysis. Of note, diarrhea is seen as a side effect of tenapanor (with its indication for the treatment of constipation) and in intestine-specific NHE3 knockout mice; however, effects on plasma Pi were not supported by this mouse model which showed enhanced and not reduced intestinal Pi uptake. Further studies indicated that the gut microbiome in mice lacking intestinal NHE3 resembles an intestinal environment favoring the competitive advantage of inflammophilic over anti-inflammatory species, something similar seen in patients with inflammatory bowel disease. This review will highlight recent developments and summarize newly gained insight from these refined models.

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Funding

This work was supported by a VA Merit Review Award IBX004968A (to T.R.). Additional support was provided by a Pilot Project from the USF Microbiomes Institute (to T.R. and J.D.R). The contents do not represent the views of the US Department of Veterans Affairs or the United States Government.

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Authors and Affiliations

  1. Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, USA

    Jessica A. Dominguez Rieg & Timo Rieg

  2. James A. Haley Veterans’ Hospital, Tampa, FL, 33612, USA

    Jessica A. Dominguez Rieg & Timo Rieg

  3. Hypertension and Kidney Research Center, University of South Florida, Tampa, FL, 33602, USA

    Jessica A. Dominguez Rieg & Timo Rieg

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  1. Jessica A. Dominguez Rieg
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  2. Timo Rieg
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J.D.R. and T.R. wrote the manuscript and prepared all figures. Both authors reviewed the manuscript.

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Correspondence to Timo Rieg.

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This article is part of the special issue on Physiology of systemic and cellular pH regulation in Pflügers Archiv—European Journal of Physiology

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Dominguez Rieg, J.A., Rieg, T. New functions and roles of the Na+-H+-exchanger NHE3. Pflugers Arch - Eur J Physiol 476, 505–516 (2024). https://doi.org/10.1007/s00424-024-02938-9

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