Na+/H+ exchangers: physiology and link to hypertension and organ ischemia

Abstract

Purpose of review: Na/H exchangers (NHEs) are ubiquitous proteins with a very wide array of physiological functions, and they are summarized in this paper in view of the most recent advances. Hypertension and organ ischemia are two disease states of paramount importance in which NHEs have been implicated. The involvement of NHEs in the pathophysiology of these disorders is incompletely understood. This paper reviews the principal findings and current hypotheses linking NHE dysfunction to hypertension and ischemia.

Recent findings: With the advent of large-scale sequencing projects and powerful in-silico analyses, we have come to know what is most likely the entire mammalian NHE gene family. Recent advances have detailed the roles of NHE proteins, exploring new functions such as anchoring, scaffolding and pH regulation of intracellular compartments. Studies of NHEs in disease models, even though not conclusive to date, have contributed new evidence on the interplay of ion transporters and the delicate ion balances that may become disrupted.

Summary: This paper provides the interested reader with a concise overview of NHE physiology, and aims to address the implication of NHEs in the pathophysiology of hypertension and organ ischemia in light of the most recent literature.

Figure 1. Functions of Na⁺/H⁺ exchangers (NHEs)

NHEs mediate the exchange of Na⁺ for H⁺ across the lipid bilayer. (a) In prokaryotes, the H⁺ gradient is used to energize extrusion of Na⁺ and thus contributes to defense against salinity. In eukaryotes, plasma membrane NHEs utilize the inward Na⁺ gradient to drive H⁺ out, hence fulfilling the role of cell pH defense. When coupled with parallel Cl⁻/base (B⁻) exchange, HB recycling, and water channels, NHEs can restore cell volume when confronted with osmotic cell shrinkage. When positioned in the lipid membrane of organelles, NHEs can regulate organellar pH and/or Na⁺ concentration. Finally, the plasma membrane locale of NHE can serve as a membrane anchor (non-transport function) and assembly site for the cytoskeleton and signaling complexes. (b) In specialized polarized epithelia, apical NHE isoforms (NHE3 and others) mediate several modes of Na⁺-coupled secretion or absorption. Coupling of NHE to H⁺-coupled transporters allows utilization of the Na⁺ gradient and conversion of H⁺-coupled transport to Na⁺-coupled transport. This is the mechanism for renal proximal tubular absorption of some organic solutes by H⁺-coupled cotransport (left absorption model; X stands for oligopeptides, amino acids, etc.) and for the secretion of others by H⁺-coupled countertransport (left secretion model; Z stands for epinephrine, norepinephrine, histamine, amiloride, etc.). NHE can also be coupled with an anion/base⁻ (B⁻) exchanger with recycling of HB (center absorption model; Y stands for chloride, urate). In the case of Cl⁻, coupled transport leads to net NaCl transport across the membrane. The extruded H⁺ can also react with a buffer such as HCO₃⁻ which is converted to CO₂. Diffusion of CO₂ across the bilayer results in net NaHCO₃ transport (right absorption model). Finally, NHE can mediate the secretion of ammonium (NH₄⁺), both by providing the H⁺ necessary to trap diffused ammonia (NH₃), and by directly transporting NH₄⁺ as a substrate (right secretion model).

Figure 2. Na⁺/H⁺ exchanger (NHE) isoforms in the mammalian kidney

NHE isoforms 1–4 and 6–9 are expressed in the kidney. NHE isoforms 1–4 and 8 are in the plasma membrane of renal epithelial cells, with precise localization to the apical or basolateral membrane. The apical isoforms are NHE3 and NHE8 in the proximal tubule, NHE3 and NHE2 in the thick ascending limb of the loop of Henle, and only NHE2 in the distal convoluted tubule and connecting tubule. The thin limbs lack detectable levels of apical NHEs, with the exception of a distinct subpopulation of juxtamedullary nephrons with long loops of Henle, which express low levels of apical NHE3. On the basolateral side, NHE1 and NHE4 are present in all nephron segments, with the exception of the macula densa and intercalated cells of the cortical collecting duct, where NHE4 is the only basolateral isoform. NHE isoforms 6, 7 and 9 are only in organellar membranes (not shown) [5••,6••,7•,8-10].

Figure 3. Theoretical links between Na⁺/H⁺ exchange overactivation and hypertension

Overactivation of Na⁺/H⁺ exchanger (NHE) 3 in the kidney may lead to salt and fluid retention, increasing the effective circulatory volume. Independently or concurrently, overactivation of NHE1 in vascular smooth muscle cells (VSMCs) may lead to intracellular Na⁺ loading, resulting in slowing or reversal of Na⁺/Ca²⁺ exchange via Na⁺/Ca²⁺ exchanger (NCX), increased cytosolic Ca²⁺ and VSMC contraction. At the same time, NHE1 activity may promote VSMC growth and proliferation, the overall result being increased peripheral resistance.

Figure 4. Theoretical model of Na⁺/H⁺ exchange in ischemia/reperfusion

(a) Ischemia leads to intracellular acidosis by anaerobic glycolysis and mitochondrial dysfunction. Na⁺/H⁺ exchange is driven by the intracellular/extracellular H⁺ gradient and allosterically activated by intracellular protons (dashed curved arrow). Acidification of the interstitium (low pH_e) partially suppresses the gradient-driven Na⁺/H⁺ exchange. At the same time, cellular ATP depletion leads to Na⁺/K⁺-ATPase dysfunction. The net result is intracellular sodium loading. Rising [Na⁺]_i slows down the Na⁺/Ca²⁺ exchanger (NCX), impairing calcium extrusion from the cell. (b) During reperfusion pH_e normalizes and Na⁺/H⁺ exchange is fully activated by allosteric regulation and ionic gradients. With cellular ATP and Na⁺/K⁺-ATPase activity still insufficient, intracellular Na⁺ rises to yet higher levels. At some point during this process, rising [Na⁺]_i leads to operation of the Na⁺/Ca²⁺ exchanger in reverse mode. NCX extrudes Na⁺ at the price of raising [Ca²⁺]_i, which can achieve deleterious levels and lead to cell injury and apoptosis. NHE, Na⁺/H⁺ exchanger.