New Insights into the Critical Importance of Intratubular Na+/H+ Exchanger 3 and Its Potential Therapeutic Implications in Hypertension

Abstract

Purpose of review: The sodium (Na⁺) and hydrogen (H⁺) exchanger 3 (NHE3), known as solute carrier family 9 member 3 (SLC9A3), mediates active transcellular Na⁺ and bicarbonate reabsorption in the small intestine of the gut and proximal tubules of the kidney. The purpose of this article is to review and discuss recent findings on the critical roles of intestinal and proximal tubule NHE3 in maintaining basal blood pressure (BP) homeostasis and their potential therapeutic implications in the development of angiotensin II (Ang II)-dependent hypertension.

Recent findings: Recently, our and other laboratories have generated or used novel genetically modified mouse models with whole-body, kidney-specific, or proximal tubule-specific deletion of NHE3 to determine the critical roles and underlying mechanisms of NHE3 in maintaining basal BP homeostasis and the development of Ang II-induced hypertension at the whole-body, kidney, or proximal tubule levels. The new findings demonstrate that NHE3 contributes to about 10 to 15 mmHg to basal blood pressure levels, and that deletion of NHE3 at the whole-kidney or proximal tubule level, or pharmacological inhibition of NHE3 at the kidney level with an orally absorbable NHE3 inhibitor AVE-0657, attenuates ~ 50% of Ang II-induced hypertension in mice. The results support the proof-of-concept hypothesis that NHE3 plays critical roles in physiologically maintaining normal BP and in the development of Ang II-dependent hypertension. Our results also strongly suggest that NHE3 in the proximal tubules of the kidney may be therapeutically targeted to treat poorly controlled hypertension in humans.

Keywords: Angiotensin II; Blood pressure; Hypertension; Na+/H+ exchanger 3; Proximal tubule.

Figure 1.

A schematic description of multifactorial mechanisms underlying the physiological regulation of blood pressure and the development of hypertension, which involves a complex genetic predisposition, neural, cardiovascular, renal and lifestyle factors. These mechanisms either act alone or interact with each other to regulate basal blood pressure homeostasis and contribute to the development of hypertension in humans.

Figure 2.

Proximal tubule-specific deletion of NHE3 does not significantly alter the intestinal structural and absorptive phenotypes in PT-Nhe3^−/− mice. A: a representative normal caecum segment between small and large intestines in a wild-type mouse (*). B: a representative cecum segment between small and large intestines in a global Nhe3^−/− mouse, showing the extremely enlarged cecum segment accumulated with a large volume of fluid content inside (*). C: a representative cecum segment between small and large intestines in a PT-Nhe3^−/− mouse, showing the lack of enlarged cecum segment and no accumulation of a large volume of fluid content in the cecum segment (*). D: the overall gut weight more than doubled in global Nhe3^−/− mice than wild-type and PT-Nhe3^−/− mice (p<0.01). E: 24 h fecal Na⁺ excretion was ~10-time higher in global Nhe3^−/− mice than wild-type and PT-Nhe3^−/− mice (p<0.01). F: accumulation of fluid content in the cecum segment was ~10 times higher in global Nhe3^−/− mice than wild-type and PT-Nhe3^−/− mice (p<0.01). There were no differences in the overall gut weight and 24 h fecal Na⁺ excretion between wild-type and PT-Nhe3^−/− mice. Reproduced from Reference [20] with copyright permission.

Figure 3.

Basal systolic, diastolic and mean arterial blood pressure in adult male and female wild-type and PT-Nhe3^−/− mice, as measured continuously for 7 days using the direct implanted telemetry technique. Please note that basal systolic, diastolic and mean arterial blood pressure were consistently about 12 ± 3 mmHg lower in male and female PT-Nhe3^−/− than wild-type mice (p<0.01). Reproduced from Reference [20] with copyright permission.

Figure 4.

Systolic, diastolic and mean arterial blood pressure responses to a high pressor dose of Ang II infusion, 1.5 mg/kg/day, i.p., via osmotic minipump in conscious, adult male and female wild-type (WT) and PT-Nhe3^−/− mice, as measured continuously for 14 days using the direct implanted telemetry technique. Please note the time-dependent increases in systolic, diastolic and mean arterial blood pressure responses in male and female WT mice, and significantly attenuated hypertensive responses to Ang II in male and female PT-Nhe3^−/− mice. **P<0.01 vs. WT time-control group; ⁺⁺P<0.01 vs. PT-Nhe3^−/− time-control group, respectively. Reproduced from Reference [21] with copyright permission.

Figure 5.

Effects of the NHE3 inhibitor AVE-0657 (20 mg/kg/day, p.o., Sanofi-Aventis) on Ang II-induced hypertension in male C57BL/6J mice infused with a slow pressor dose of Ang II at 0.5 mg/kg/day, i.p., for 2 weeks. AVE-0657 is an orally absorbable NHE3 inhibitor which is filtered by the glomerulus into the proximal tubules to inhibit NHE3 in the apical membranes (A). AVE-0657 significantly attenuated Ang II-induced hypertension (B), and the response was associated with a significant natriuretic response after 7 days' administration (D), without affecting 24 h urinary K⁺ (E) or fecal Na⁺ excretion (F). **P<0.01 vs. time-control group; ⁺⁺P<0.01 vs. Ang II group. Reproduced from Reference [21] with copyright permission.

Figure 6.

The important role of NHE3 in the proximal tubules of the kidney in the development of Ang II-dependent hypertension. We hypothesize that the circulating and intratubular Ang II binds to high affinity and high density of AT₁ receptors on both apical and basolateral membranes of the proximal tubules and activates downstream signaling pathways such as protein kinase Cα (PKCα) to increase the expression and activity of NHE3 and Na⁺/K⁺-ATPase. The sustained upregulation of NHE3 and Na⁺/K⁺-ATPase by Ang II stimulates proximal tubular Na⁺ reabsorption, increases body Na⁺ and fluid retention, impairs the pressure-natriuresis response, and ultimately contributes to the development of Ang II-dependent hypertension. At the early stage of hypertension, the rise in arterial pressure induces the pressure-natriuresis response to prevent further increase in blood pressure. However, the pressure-natriuresis response resets to higher pressures during established hypertension. Reproduced from Reference [21] with copyright permission.