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

Abstract

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.

Blood Gene Expression Profile Predicts Response to Antipsychotics

“…The gene with the highest predictive value, SLC9A3 , is a Na/H exchanger and belongs to several pathways such as the transmembrane transportation of small molecules and the SLC-mediated transmembrane transport that facilitate the movement of a specific substrate either against or following their concentration gradient. Currently, there are novel drugs being developed targeting SLC9A3 that could be of interest for the field of schizophrenia (Dominguez Rieg et al, 2016 ). The second best predictor is HMOX1 , or Heme oxygenase, an essential enzyme in heme catabolism, that cleaves heme to form biliverdin, which is subsequently converted to bilirubin by biliverdin reductase, and carbon monoxide, a putative neurotransmitter.…”

Role of the sodium‐hydrogen exchanger in mediating the renal effects of drugs commonly used in the treatment of type 2 diabetes

“…The sodium‐hydrogen exchanger isoform 1 (NHE1) is present in all cells, where it plays an important physiological role in maintaining cell volume and acidity within narrow limits . By contrast, the sodium‐hydrogen exchanger isoform 3 (NHE3) is limited to the apical surface of renal and gastrointestinal epithelial cells, where it mediates sodium reabsorption . The action of NHE3 accounts for a majority of the sodium reuptake that follows glomerular filtration …”

“…Similarly, kidney‐specific NHE3 knockout models have been developed, and renal tubular NHE3 can be selectively inhibited by adenoviral promoter fragments . The trafficking of renal tubular NHE3 involves specific phosphorylation sites, which may be selectively targeted by novel compounds . Alternatively, innovative therapeutic agents might focus on interfering with the binding proteins or kinases that are required for the phosphorylation, trafficking or membrane localization of NHE3 in renal tubular cells .…”

“…12 By contrast, the sodium-hydrogen exchanger isoform 3 (NHE3) is limited to the apical surface of renal and gastrointestinal epithelial cells, where it mediates sodium reabsorption. 13 The action of NHE3 accounts for a majority of the sodium reuptake that follows glomerular filtration. 14 Type 2 diabetes is characterized by an increase in the activity of both NHE1 and NHE3 in the kidney.…”

“…241 The trafficking of renal tubular NHE3 involves specific phosphorylation sites, 242 which may be selectively targeted by novel compounds. 13 Alternatively, innovative therapeutic agents might focus on interfering with the binding proteins or kinases that are required for the phosphorylation, trafficking or membrane localization of NHE3 in renal tubular cells. 26,[243][244][245][246] The development of such novel agents might allow physicians to directly address one of the primary mechanisms responsible for the glomerular hyperfiltration that leads to diabetic nephropathy.…”