Novel developments in differentiating the role of renal and intestinal sodium hydrogen exchanger 3

The Na⁺/H⁺ exchanger isoform 3 (NHE3) facilitates Na⁺ absorption and H⁺ secretion and is expressed in the intestine, proximal tubule, and thick ascending limb of the kidney. While the function of NHE3 for Na⁺ and [Formula: see text](re)absorption has been defined using conventional NHE3 knockout mice (NHE3^-/-), the recent generation of conditional NHE3 knockout mice started to give critical new insight into the role of this protein by allowing for temporal and spatial control of NHE3 expression. For example, in contrast to NHE3^-/- mice, knockout of NHE3 in the S1 and S2 segments of the proximal tubule or along the entire tubule/collecting duct does not cause any lethality. Nonabsorbable NHE3 inhibitors have been developed, and preclinical as well as clinical trials indicate possible pharmacological use in fluid overload, hypertension, chronic kidney disease, hyperphosphatemia, and constipation. Some of the therapeutic considerations seem to be directly related to the pharmacodynamic properties of these drugs; however, little is known about the effects of these nonabsorbable NHE3 inhibitors on intestinal phosphate transport and the mechanisms so far remain elusive. This review focuses on novel findings of NHE3 in the intestine and the kidney as well as novel drug developments targeting NHE3.