Luminal Na+/H+ exchange in the proximal tubule

Abstract

The proximal tubule is critical for whole-organism volume and acid-base homeostasis by reabsorbing filtered water, NaCl, bicarbonate, and citrate, as well as by excreting acid in the form of hydrogen and ammonium ions and producing new bicarbonate in the process. Filtered organic solutes such as amino acids, oligopeptides, and proteins are also retrieved by the proximal tubule. Luminal membrane Na + /H + exchangers either directly mediate or indirectly contribute to each of these processes. Na + /H + exchangers are a family of secondary active transporters with diverse tissue and subcellular distributions. Two isoforms, NHE3 and NHE8, are expressed at the luminal membrane of the proximal tubule. NHE3 is the prevalent isoform in adults, is the most extensively studied, and is tightly regulated by a large number of agonists and physiological conditions acting via partially defined molecular mechanisms. Comparatively little is known about NHE8, which is highly expressed at the lumen of the neonatal proximal tubule and is mostly intracellular in adults. This article discusses the physiology of proximal Na + /H + exchange, the multiple mechanisms of NHE3 regulation, and the reciprocal relationship between NHE3 and NHE8 at the lumen of the proximal tubule. KeywordsAcid-based balance; pH regulation; Volume regulation; Sodium transport; Bicarbonate transport; Chloride transport; Sodium-hydrogen exchange; Sodium-proton exchange Na + /H + exchange in biology Na + /H + exchangers (NHEs) are universally present in prokaryotes, lower eukaryotes, and higher eukaryotes, including fungi, plants, and animals [1]. In prokaryotes, fungi and plants, the transmembrane proton electrochemical gradient (ΔμH + ) energizes the extrusion of Na + from the cytoplasm. Plasma membrane NHEs characterized to date in animal cells utilize the NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscriptinward Na + gradient created by the activity of Na + /K + -adenosine triphosphatase (ATPase) to extrude H + against its electrochemical gradient in an electroneutral fashion.All NHEs are members of the very large superfamily of monovalent cation-proton antiporters (CPA), which is divided phylogenetically in the CPA1, CPA2, and NaT-DC transporter families [1,2]. Nine NHE isoforms (NHE1-9) belonging to the CPA1 family and having different tissue and subcellular distribution (Table 1) have been described to date in the human genome [1,3,4]. In addition, the human genome contains a sperm-specific NHE (a member of the NaT-DC family) with demonstrated NHE activity [1,5,6], as well as two genes termed NHA1 and NHA2 (members of the CPA2 family) which are more closely related to prokaryotic Na + /H + exchangers [1] ( Table 1). The expression and function of NHA2 have been recently confirmed [7,8]. Brett et al. [1] presented an extensive phylogenetic classification of NHEs using 118 eukaryotic NHE genes of the CPA1 family. Based on sequence, cellular location, ion selectivity, and inhibitor specificity, NHEs can be divided into two majo...

ANG II, ANG-(1-7), ALDO and AVP biphasic effects on Na+/H+ transport: the role of cellular calcium

“…In the nephron, individual NHE isoforms have different functions. These functions are reflected in their differential expression along the segments of the nephron, their localization in renal epithelial cells at the basolateral (e.g., isoform NHE1) or apical surface (e.g., isoform NHE3), and their activation in response to distinct agonists [4][5][6][7][8][9][10][11][12][13].…”

“…Therefore, CaMKII constitutively binds to, phosphorylates, and inhibits NHE3 via a NHERF2 protein-dependent process [48]. Because it has multiple functions, NHE3 is regulated by a wide variety of agonists in response to physiological conditions [4,13,51].…”

“…In this study, we used fluorescent probes to measure the recovery rate of intracellular pH [(pHi)r] after inducing the acidification of the pHi via an NH 4 Cl pulse, and we also monitored the [Ca 2+ ]i. Figure 1 shows that in the controls, the (pHi)r was 0.088 ± 0.014 pH units/min [114].…”

A molecularly guided tour along the nephron

“…The Na + ,H + exchanger, one of the major luminal transporters, is accommodating many transport processes in this nephron segment. The molecular physiology and regulation of this exchanger is elegantly described by Bobulescu and Moe [3]. Vesicular Cl − /H + exchangers are expressed in the proximal tubule, and malfunction of these proteins impairs the endocytosis process in this segment explaining the primary defect in Dent's disease as outlined by Jentsch and coworkers [11].…”

“…In addition, the kidney produces hormones and proteins exerting important general physiological roles. For instance, the biological active form of vitamin D is mainly produced in the kidney through the conversion of 25-hydroxyvitamin D 3 to 1,25-dihydroxyvitamin D 3 by the renal enzyme 25-hydroxyvitamin D-1-α-hydroxylase. In addition, the antiaging hormone klotho is primarily produced in the kidney and controls overall mineral metabolism.…”