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

Authors
  • Zhuo, Jia Long1
  • Soleimani, Manoocher2
  • Li, Xiao Chun1
  • 1 Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA, 70112, USA , New Orleans (United States)
  • 2 University of New Mexico College of Medicine, Albuquerque, NM, 87131, USA , Albuquerque (United States)
Type
Published Article
Journal
Current Hypertension Reports
Publisher
Springer-Verlag
Publication Date
Jun 10, 2021
Volume
23
Issue
6
Identifiers
DOI: 10.1007/s11906-021-01152-7
Source
Springer Nature
Keywords
Disciplines
  • Topical Collection on Hypertension and the Kidney
License
Yellow

Abstract

Purpose of ReviewThe 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 FindingsRecently, 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.SummaryThe 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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