Sodium-hydrogen exchanger 1 and 3 (NHE1/NHE3)

Sodium-hydrogen exchanger 1 (NHE1) and 3 (NHE3) are integral membrane proteins that regulate ion homeostasis by exchanging extracellular sodium for intracellular protons. NHE1 is ubiquitously expressed and serves as a primary regulator of intracellular pH and cell volume, particularly in the heart where its overactivation is linked to cardiac injury and remodeling. NHE3 is predominantly localized to the apical membranes of the renal proximal tubule and intestinal epithelia, where it mediates the majority of sodium and water reabsorption. The dual targeting of NHE1 and NHE3 is a significant therapeutic strategy in cardiometabolic diseases, as their simultaneous upregulation promotes fluid retention and heart failure progression. Additionally, NHE3 inhibition in the gut reduces paracellular phosphate absorption, making it a target for managing hyperphosphatemia in chronic kidney disease. Therapeutic modulation of NHE1 and NHE3, either through selective inhibitors like tenapanor or pleiotropic agents like SGLT2 inhibitors, offers a multi-organ approach to treating hypertension, chronic kidney disease, and congestive heart failure.

Other names

SLC9A1 and SLC9A3Sodium/proton exchanger 1 and 3Na+/H+ exchanger 1 and 3Solute carrier family 9 member 1 and 3NHE-1 and NHE-3

Inhibition of the electroneutral exchange of extracellular sodium for intracellular protons, leading to reduced sodium reabsorption in the kidney and intestine and preventing sodium-calcium overload in the heart.