The Na+/H+ Exchanger 3 in the Intestines and the Proximal Tubule of the Kidney: Localization, Physiological Function, and Key Roles in Angiotensin II-Induced Hypertension

Abstract

The sodium (Na+)/hydrogen (H+) exchanger 3 (NHE3) is one of the most important Na+/H+ antiporters in the small intestines of the gastrointestinal tract and the proximal tubules of the kidney. The roles of NHE3 in the regulation of intracellular pH and acid–base balance have been well established in cellular physiology using in vitro techniques. Localized primarily on the apical membranes in small intestines and proximal tubules, the key action of NHE3 is to facilitate the entry of luminal Na+ and the extrusion of intracellular H+ from intestinal and proximal tubule tubular epithelial cells. NHE3 is, directly and indirectly, responsible for absorbing the majority of ingested Na+ from small and large intestines and reabsorbing >50% of filtered Na+ in the proximal tubules of the kidney. However, the roles of NHE3 in the regulation of proximal tubular Na+ transport in the integrative physiological settings and its contributions to the basal blood pressure regulation and angiotensin II (Ang II)-induced hypertension have not been well studied previously due to the lack of suitable animal models. Recently, novel genetically modified mouse models with whole-body, kidney-specific, or proximal tubule-specific deletion of NHE3 have been generated by us and others to determine the critical roles and underlying mechanisms of NHE3 in maintaining basal body salt and fluid balance, blood pressure homeostasis, and the development of Ang II-induced hypertension at the whole-body, kidney, or proximal tubule levels. The objective of this invited article is to review, update, and discuss recent findings on the critical roles of intestinal and proximal tubule NHE3 in maintaining basal blood pressure homeostasis and their potential therapeutic implications in the development of angiotensin II (Ang II)-dependent hypertension.

Dietary sodium enhances the expression of SLC4 family transporters, IRBIT, L-IRBIT, and PP1 in rat kidney: Insights into the molecular mechanism for renal sodium handling

“…NHE3 activity is stimulated by angiotensin II (Ang II) in a manner dependent on IRBIT and CaMKIIα ( He et al, 2010 ). NHE3 in the proximal tubule is shown to be involved in the development of hypertension induced by Ang II ( Nwia et al, 2022 ). The apical SLC26A6 in the proximal tubule plays a dispensible role in the regulation of NaCl homeostasis in the body ( Knauf et al, 2001 ; Knauf et al, 2019 ).…”

Gut microbiota dependant trimethylamine N-oxide and hypertension

“…NHE3 is also found in the proximal renal tubule to regulate sodium and water absorption ( Curthoys, 2007 ). Gut NHE3 plays the most important role in regulating sodium absorption, mainly in the small intestines, and when this sodium is filtered in the kidneys, more than 50% of it is reabsorbed by the renal NH3 in the proximal tubules ( Nwia et al, 2022 ).…”

Reducing Oxygen Demand to Alleviate Acute Kidney Injury

“…It has been well described that angiotensin II stimulates NHE3, which contributes to angiotensin II-induced hypertension [126][127][128]. Angiotensin II increases the levels of NHE3 mRNA and protein [129], stimulates cellular trafficking and exocytotic membrane insertion [130,131], counteracts inhibitory phosphorylation by cAMP/PKA [132], and increases transport activity [133].…”