Novel Treatments from Inhibition of the Intestinal Sodium–Hydrogen Exchanger 3

Abstract

Plasma membrane sodium–hydrogen exchangers (NHE) transport Na + into cells in exchange for H + . While there are nine isoforms of NHE in humans, this review focuses on the NHE3 isoform, which is abundantly expressed in the gastrointestinal tract, where it plays a key role in acid–base balance and water homeostasis. NHE3 inhibition in the small intestine results in luminal sodium and water retention, leading to a general decrease in paracellular water flux and diffusional driving force, reduced intestinal sodium absorption, and increased stool sodium excretion. The resulting softer and more frequent stools are the rationale for the development of tenapanor as a novel, first-in-class NHE3 inhibitor to treat irritable bowel syndrome with constipation. NHE3 also has additional therapeutic implications in nephrology. Inhibition of intestinal NHE3 also lowers blood pressure by reducing intestinal sodium absorption. Perhaps, the most novel effect is its ability to decrease intestinal phosphate absorption by inhibiting the paracellular phosphate absorption pathway. Therefore, selective pharmacological inhibition of NHE3 could be a potential therapeutic strategy to treat not only heart failure and hypertension but also hyperphosphatemia. This review presents an overview of the molecular and physiological functions of NHE3 and discusses how these functions translate to potential clinical applications in nephrology.

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

“…Against this background, we have hypothesized that therapeutically targeting NHE3 may present us a new additional pathway to treat human hypertension. As proof-of-concept studies, gastrointestinal NHE3 inhibitors have been developed to treat several disease targets including hypertension, constipation, and hyperphosphatemia in elder patients ( Linz et al, 2012 , 2016 , 2020 ; Li et al, 2019b ; Kovesdy et al, 2021 ). One NHE3 blocker, SAR218034 (SAR), has been shown to increase fecal sodium excretion and decrease systolic blood pressure in lean old SHRs ( Linz et al, 2012 ).…”

Impact of dietary sodium restriction on falls among middle‐aged and older adults: Results of an 8‐year longitudinal study

“…Because intestinal absorption of water depends on the presence of sodium in the intestinal lumen, restriction of sodium may also play a role in determining a negative water balance 36 . Thus, salt restriction may facilitate water reabsorption from the stool in the rectum, leading to dry and hard stools, impeding peristalsis, and resulting in a decrease in bowel movement frequency 37 . Constipation may be an important risk factor for anorexia 38,39 and impaired functional status in older adults, 40,41 both of which relate to decreased muscle mass and strength, 42,43 which can cause falls 44 .…”

“…36 Thus, salt restriction may facilitate water reabsorption from the stool in the rectum, leading to dry and hard stools, impeding peristalsis, and resulting in a decrease in bowel movement frequency. 37 Constipation may be an important risk factor for anorexia 38,39 and impaired functional status in older adults, 40,41 both of which relate to decreased muscle mass and strength, 42,43 which can cause falls. 44 Sodium is also essential for the formation of action potentials.…”

The Role of Plasma Membrane Sodium/Hydrogen Exchangers in Gastrointestinal Functions: Proliferation and Differentiation, Fluid/Electrolyte Transport and Barrier Integrity

“…Independently of the above-mentioned coupling with di-/tripeptide absorption, NHE3 activity represents the major mechanism of intestinal Na + absorption accompanied by mostly paracellular water uptake ( Karasov, 2017 ). It thus contributes significantly to body fluid and blood pressure homeostasis as well as acid-base regulation ( Pedersen and Counillon, 2019 ; Kovesdy et al, 2021 ; Zhuo et al, 2021 ) which is supported by a number of studies using elaborate NHE3 knockout mouse models, such as tissue-specific ( Dominguez Rieg et al, 2016 ) or tamoxifen-inducible intestinal epithelial cell-specific NHE3 knockout mice ( Xue et al, 2020 ), or specific drugs such as the first-in-class NHE3 inhibitor tenapanor ( Spencer et al, 2014 ; Yu et al, 2019 ; Zhou et al, 2021 ). Treating NHE2 knockout mice with tenapanor revealed that NHE2 contributes to colonic fluid absorption only marginally, if at all ( Nikolovska et al, 2022 ).…”

“…Trafficking between plasma membrane and compartments is a common method of acute regulation. As for NHE3, trafficking represents a temporary compartmentalization of transport activity, i.e., NHE3 remains active in recycling endosomes ( D'Souza et al, 1998 ; Kovesdy et al, 2021 ). In addition to a constitutively recycling NHE3 population, another intracellular population seems to be located in storage compartments, potentially waiting to be recruited to the cell surface when acutely needed, e.g., in order to reabsorb Na + in proximal renal tubules ( Alexander et al, 2005 ; Alexander and Grinstein, 2009 ).…”