SLC9A3 is a sodium–hydrogen antiporter. It is found in the tubulus proximal of the nephron of the kidney and in the apical membrane of enterocytes of the intestine. It is primarily responsible for maintaining the balance of sodium.



An Overview of SLC9A3

SLC9A3 (Solute Carrier Family 9, subfamily A (NHE3, cation proton antiporter 3), member 3; region 5p15.3) gene encodes a protein that transports sodium ions and hydrogen. SLC9A3 protein plays a key role in pH regulation, functions from the elimination of acid produced by active metabolism, and plays a role in signal transduction, in which a chemical gradient of ions is emitted to absorb the sodium ions. Therefore, SLC9A3 is mainly responsible for maintaining the balance of sodium. SLC9A3 is mainly located in the renal membrane of the proximal end of the nephron and in the apical membrane of intestinal cells of the intestine.

SLC9A3 and diseases

Variants in the SLC9A3 gene provide evidence for their modulatory effects on cystic fibrosis (CF) by interacting with the cystic fibrosis transmembrane conductance regulator (CFTR) gene to the susceptibility to bacterial infection and the severity of lung disease. CF manifests with clinical and histopathological variability depending on environmental and genetic factors. The rs17563161 variant (intron variant) is associated with the digestive tract and lung disease in CF. Besides, SLC9A3 plays a functional role in dilated intercellular spaces formation, and pharmacologic interventions targeting SLC9A3 function can inhibit the histopathologic manifestations of patients with eosinophilic esophagitis. SLC9A3 expression was increased within the basal layer of esophageal biopsy specimens from patients with eosinophilic esophagitis, and expression is positively correlated with disease severity and dilated intercellular spaces.

Inhibition of SLC9A3

Tenapanor acts as an inhibitor of the sodium-proton exchanger NHE3 encoded by SLC9A3. When administered orally, tenapanor selectively limits sodium intake from the gut, limits sodium supply from food, and thereby reduces sodium in the body. It can be used to treat chronic kidney disease and high blood pressure due to excess sodium in the diet.


Pereira, S. V., Ribeiro, J. D., Bertuzzo, C. S., & Marson, F. A. (2018). Interaction among variants in the SLC gene family (SLC6A14, SLC26A9, SLC11A1, and SLC9A3) and CFTR mutations with clinical markers of cystic fibrosis. Pediatric pulmonology.