International Journal of Nephrology and Renovascular Disease (Dec 2021)
Novel Treatments from Inhibition of the Intestinal Sodium–Hydrogen Exchanger 3
Abstract
Csaba P Kovesdy,1 Adebowale Adebiyi,2 David Rosenbaum,3 Jeffrey W Jacobs,3 L Darryl Quarles1 1Division of Nephrology, University of Tennessee Health Science Center, Memphis, TN, USA; 2Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, USA; 3Medical Affairs, Ardelyx, Inc., Boston, MA, USACorrespondence: Csaba P KovesdyUniversity of Tennessee Health Science Center, Memphis VA Medical Center, 956 Court Avenue, Room B222, Memphis, TN, 38163, USATel +901 448-2985Email [email protected]: 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.Keywords: sodium–hydrogen exchanger 3, sodium–hydrogen exchanger 3 inhibitors, paracellular phosphate absorption pathway, hyperphosphatemia, chronic kidney disease, heart failure
