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New Insights into the Critical Importance of Intratubular Na+/H+ Exchanger 3 and Its Potential Therapeutic Implications in Hypertension

  • Hypertension and the Kidney (RM Carey , Section Editor)
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Abstract

Purpose of Review

The sodium (Na+) and hydrogen (H+) exchanger 3 (NHE3), known as solute carrier family 9 member 3 (SLC9A3), mediates active transcellular Na+ and bicarbonate reabsorption in the small intestine of the gut and proximal tubules of the kidney. The purpose of this article is to review and discuss recent findings on the critical roles of intestinal and proximal tubule NHE3 in maintaining basal blood pressure (BP) homeostasis and their potential therapeutic implications in the development of angiotensin II (Ang II)–dependent hypertension.

Recent Findings

Recently, our and other laboratories have generated or used novel genetically modified mouse models with whole-body, kidney–specific, or proximal tubule–specific deletion of NHE3 to determine the critical roles and underlying mechanisms of NHE3 in maintaining basal BP homeostasis and the development of Ang II–induced hypertension at the whole-body, kidney, or proximal tubule levels. The new findings demonstrate that NHE3 contributes to about 10 to 15 mmHg to basal blood pressure levels, and that deletion of NHE3 at the whole-kidney or proximal tubule level, or pharmacological inhibition of NHE3 at the kidney level with an orally absorbable NHE3 inhibitor AVE-0657, attenuates ~ 50% of Ang II–induced hypertension in mice.

Summary

The results support the proof-of-concept hypothesis that NHE3 plays critical roles in physiologically maintaining normal BP and in the development of Ang II–dependent hypertension. Our results also strongly suggest that NHE3 in the proximal tubules of the kidney may be therapeutically targeted to treat poorly controlled hypertension in humans.

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Acknowledgements

All experiments were performed and data collected in the laboratory of Dr. Jia Zhuo at the University of Mississippi Medical Center in Jackson, Mississippi, and Tulane University School of Medicine, in New Orleans, Louisiana, respectively. We specifically thank Dr. Gary Shull of the University of Cincinnati College of Medicine for generously providing us with breeding pairs of global Nhe3−/− and tgNhe3−/− mice, Dr. Manoocher Soleimani of the University of Cincinnati School of Medicine for generously providing us with breeding pairs of NHE3-floxed mice, Drs. Isabelle Rubera and Michell Tauc from the Laboratoire de Physiomédecine Moléculaire, LP2M, UMR-CNRS 7370, Université Côte d'Azur, Nice Cedex 2, France (I.R., M.T.) for generously providing us with breeding pairs of iL1-sglt2-Cre mouse strain, and Sanofi-Aventis for providing the absorbable NHE3 inhibitor AVE-0657 for our studies. We also thank our past and present technicians and postdoctoral fellows for their excellent technical support and assistance over many years.

Funding

This work was supported in part by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (2R01DK102429-03A1, 2R01DK067299-10A1, and 1R01DK102429-01) and National Heart, Lung, And Blood Institute (1R56HL130988-01) to Dr. Jia L. Zhuo.

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Authors and Affiliations

  1. Tulane Hypertension and Renal Center of Excellence and Department of Physiology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA, 70112, USA

    Jia Long Zhuo & Xiao Chun Li

  2. Division of Nephrology, Department of Internal Medicine, University of New Mexico College of Medicine, Albuquerque, NM, 87131, USA

    Manoocher Soleimani

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  1. Jia Long Zhuo
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  3. Xiao Chun Li
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Contributions

Conceptualization: Jia Zhuo and Xiao Li; writing draft preparations: Jia Zhuo and Xiao Li; review and editing: Jia Zhuo, Manoocher Soleimani, and Xiao Li; finalization: Jia Zhuo, Manoocher Soleimani, and Xiao Li

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Correspondence to Jia Long Zhuo or Xiao Chun Li.

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This article does not contain any studies on humans. All animal studies from the authors and cited in this article were approved by the IACUC of the University of Mississippi Medical Center and Tulane University School of Medicine.

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Zhuo, J.L., Soleimani, M. & Li, X.C. New Insights into the Critical Importance of Intratubular Na+/H+ Exchanger 3 and Its Potential Therapeutic Implications in Hypertension. Curr Hypertens Rep 23, 34 (2021). https://doi.org/10.1007/s11906-021-01152-7

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