Kovesdy Csaba P, Adebiyi Adebowale, Rosenbaum David, Jacobs Jeffrey W, Quarles L Darryl
Division of Nephrology, University of Tennessee Health Science Center, Memphis, TN, USA.
Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, USA.
Int J Nephrol Renovasc Dis. 2021 Dec 1;14:411-420. doi: 10.2147/IJNRD.S334024. eCollection 2021.
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.
质膜钠氢交换体（NHE）将Na转运到细胞内以交换H。人类有9种NHE亚型，本综述重点关注NHE3亚型，它在胃肠道中大量表达，在酸碱平衡和水稳态中起关键作用。小肠中的NHE3受到抑制会导致肠腔钠和水潴留，导致细胞旁水通量和扩散驱动力普遍降低，肠道钠吸收减少，粪便钠排泄增加。由此产生的更软且更频繁的粪便，是开发替纳帕诺作为一种新型的、同类首创的NHE3抑制剂来治疗便秘型肠易激综合征的理论依据。NHE3在肾脏病学中也有其他治疗意义。抑制肠道NHE3还可通过减少肠道钠吸收来降低血压。也许，最新颖的作用是它能够通过抑制细胞旁磷酸盐吸收途径来减少肠道磷酸盐吸收。因此，选择性药理抑制NHE3可能是一种潜在的治疗策略，不仅可用于治疗心力衰竭和高血压，还可用于治疗高磷血症。本综述概述了NHE3的分子和生理功能，并讨论了这些功能如何转化为肾脏病学中的潜在临床应用。
