Genetic and genomic evidence for an important role of the Na+/H+ exchanger 3 in blood pressure regulation and angiotensin II-induced hypertension

Abstract

The sodium (Na⁺)/hydrogen (H⁺) exchanger 3 (NHE3) and sodium-potassium adenosine triphosphatase (Na⁺/K⁺-ATPase) are two of the most important Na⁺ transporters in the proximal tubules of the kidney. On the apical membrane side, NHE3 primarily mediates the entry of Na⁺ into and the exit of H⁺ from the proximal tubules, directly and indirectly being responsible for reabsorbing ~50% of filtered Na⁺ in the proximal tubules of the kidney. On the basolateral membrane side, Na⁺/K⁺-ATPase serves as a powerful engine driving Na⁺ out of, while pumping K⁺ into the proximal tubules against their concentration gradients. While the roles of NHE3 and Na⁺/K⁺-ATPase in proximal tubular Na⁺ transport under in vitro conditions are well recognized, their respective contributions to the basal blood pressure regulation and angiotensin II (ANG II)-induced hypertension remain poorly understood. Recently, we have been fortunate to be able to use genetically modified mouse models with global, kidney- or proximal tubule-specific deletion of NHE3 to directly determine the cause and effect relationship between NHE3, basal blood pressure homeostasis, and ANG II-induced hypertension at the whole body, kidney and/or proximal tubule levels. The purpose of this article is to review the genetic and genomic evidence for an important role of NHE3 with a focus in the regulation of basal blood pressure and ANG II-induced hypertension, as we learned from studies using global, kidney- or proximal tubule-specific NHE3 knockout mice. We hypothesize that NHE3 in the proximal tubules is necessary for maintaining basal blood pressure homeostasis and the development of ANG II-induced hypertension.

Keywords: NHE3; angiotensin II; hypertension; intestines; kidney; proximal tubule.

Fig. 1.

Structural and absorptive phenotypes of small intestines of the digestive system in mutant mice with global (Nhe3^−/−), kidney- (tgNhe3^−/−), and proximal tubule-specific deletion of NHE3 (PT-Nhe3^−/−). A: a representative normal cecum 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 (*). Please note that the overall gut weight more than double in global Nhe3^−/− mice than wild-type (WT) and PT-Nhe3^−/− mice (D), whereas 24 h fecal Na⁺ excretion (E) and accumulation of fluid content (F) are ~10 times higher in global Nhe3^−/− mice than WT and PT-Nhe3^−/− mice. These results strongly suggest that there is no off-side NHE3 deletion in small intestines in PT-Nhe3^−/− mice. Reproduced from reference (70) with permission.

Fig. 2.

The basal blood pressure phenotype in genetically modified mice with global (Nhe3^−/−), kidney- (tgNhe3^−/−), and proximal tubule-specific deletion of NHE3 (PT-Nhe3^−/−). Basal systolic and intra-arterial blood pressure is significantly lower in adult male Nhe3^−/−, tgNhe3^−/− and PT-Nhe3^−/−mice. Blood pressure was measured continuously for 7 days by the direct implanted telemetry technique. Modified from references (–70) with permission.

Fig. 3.

The pressure-natriuresis response in male wild-type and PT-Nhe3^−/− mice. In response to an increase of ~30 mmHg in renal perfusion pressure, the pressure-natriuresis response increased ~5-fold in male wild-type mice, whereas the response increased ~8-fold in male PT-Nhe3^−/− mice (**P < 0.01). Both net urinary Na⁺ excretion and as a response to 10 mmHg blood pressure increase were significantly higher in male PT-Nhe3^−/− mice (P < 0.01; n = 10) than in wild-type mice (P < 0.01; n = 8). Reproduced from reference (70) with permission.

Fig. 4.

The systolic blood pressure responses to ANG II are attenuated in adult male conscious global Nhe3^−/− and “kidney-selective” tgNhe3^−/−mice, compared with wild-type mice (A, **P < 0.01 vs. the same groups' respective control or baseline levels; ⁺⁺P < 0.01 vs. the corresponding wild-type groups with the same treatment), and the compensatory upregulation of basal water (aquaporin 1, AQP1) and major Na⁺ cotransporter proteins, including Na⁺/${\text{HCO}}_3^{-}$ and Na⁺/K⁺-ATPase α1, in the proximal tubules of global Nhe3^−/− mice (B, ⁺⁺P < 0.01 vs. wild type). Reproduced from references (68, 69).

Fig. 5.

A schematic hypothesis that systemic and tissue ANG II activates AT₁ receptors on the apical and basolateral membranes of the proximal tubules of the kidney and downstream signaling pathways to increase the expression and activity of NHE3 and Na⁺/K⁺-ATPase, which stimulates proximal tubular Na⁺ reabsorption, causes body Na⁺ and fluid retention, and induces ANG II-dependent hypertension. Increased arterial pressure will induce the pressure-natriuresis response to prevent further increase in blood pressure at the very early stage of hypertension. However, the initially increased pressure-natriuresis response is insufficient to restore blood pressure to normal in established ANG II-induced hypertension due to the resetting of the response to higher pressures.