Role of the Na⁺/H⁺exchanger 3 in angiotensin II-induced hypertension in NHE3-deficient mice with transgenic rescue of NHE3 in small intestines

Abstract

The role of Na+/H+ exchanger 3 (NHE3) in the kidney in angiotensin II (ANG II)-induced hypertension remains unknown. The present study used global NHE3-deficient mice with transgenic rescue of the Nhe3 gene in small intestines (tgNhe3−/−) to test the hypothesis that genetic deletion of NHE3 selectively in the kidney attenuates ANG II-induced hypertension. Six groups of wild-type (tgNhe3+/+) and tgNhe3−/− mice were infused with either vehicle or ANG II (1.5 mg/kg/day, i.p., 2 weeks, or 10 nmol/min, i.v., 30 min), treated with or without losartan (20 mg/kg/day, p.o.) for 2 weeks. Basal systolic blood pressure (SBP) and mean intra-arterial blood pressure (MAP) were significantly lower in tgNhe3−/− mice (P < 0.01). Basal glomerular filtration rate, 24 h urine excretion, urinary Na+ excretion, urinary K+ excretion, and urinary Cl− excretion were significantly lower in tgNhe3−/− mice (P < 0.01). These responses were associated with significantly elevated plasma ANG II and aldosterone levels, and marked upregulation in aquaporin 1, the Na+/HCO3 cotransporter, the α1 subunit isoform of Na+/K+-ATPase, protein kinase Cα, MAP kinases ERK1/2, and glycogen synthase kinase 3 α/β in the renal cortex of tgNhe3−/− mice (P < 0.01). ANG II infusion markedly increased SBP and MAP and renal cortical transporter and signaling proteins in tgNhe3+/+, as expected, but all of these responses to ANG II were attenuated in tgNhe3−/− mice (P < 0.01). These results suggest that NHE3 in the kidney is necessary for maintaining normal blood pressure and fully developing ANG II-dependent hypertension.

Renal tubular NHE3 is required in the maintenance of water and sodium chloride homeostasis

“…16–18 Vice versa, inhibiting angiotensin-converting enzyme induced a redistribution of NHE3 from enriched microvillar membranes to intermicrovillar membrane-enriched fractions. 19 The role of NHE3 is supported by recent studies using NHE3 −/− 20 and tgNHE3 −/− 21 mice that have an absence of AngII-induced hypertension. Of note, in humans, NHE3 polymorphisms have not been linked to essential hypertension.…”

Recent Updates on the Proximal Tubule Renin-Angiotensin System in Angiotensin II-Dependent Hypertension

“…Lower basal blood pressure occurred in spite of significantly elevated plasma ANG II and aldosterone levels, and marked upregulation in aquaporin 1, the Na + /HCO3-cotransporter, the α1 subunit isoform of Na + /K + -ATPase, protein kinase Cα, MAP kinases ERK1/2, and glycogen synthase kinase 3 α/β in the renal cortex in these mice ( p < 0.01). These results suggest that these compensatory RAS and transporter responses were insufficient to maintain normal basal blood pressure in these mice [30••, 31••]. In response to a pressor dose of ANG II infusion for 2 weeks (1.5 mg/kg/day, i.p.…”

“…Indeed, the proximal tubules are responsible for reabsorbing ~70 % of filtered Na + and H 2 O from the glomeruli; thus, sustained increases in Na + reabsorption in the proximal tubules by a few percentage points will ultimately cause Na + retention, with consequence of increased body fluid volume and blood pressure. Several key factors play important roles in regulating Na + reabsorption in the proximal tubules of the kidney and blood pressure, namely angiotensin II (ANG II) via AT 1 receptors [18, 20••, 22•, 23••], ANG II/ANG III via AT 2 receptors [24, 25, 26•], and the Na + and proton (H + ) exchanger subtype 3 (NHE3) [27–29, 30••, 31••, 32••]. Other factors, such as dopamine via D 1 –D 5 receptors [33–35], endothelin 1 via ET A and ET B receptors [36–39], atrial natriuretic peptides via NPR A and NPR B receptors [40–43], and renal sympathetic nervous activity [44–46] are also involved in the regulation of proximal tubule Na + reabsorption and blood pressure; nevertheless, the roles of these humoral factors are beyond the scope of discussions in this article.…”

“…The objectives of this article are to review recent research advances in studying the roles of circulating and proximal tubule cellular ANG II via AT 1 receptors [18, 20••, 21••, 22•, 23••], ANG II/ANG III via AT 2 receptors [24, 25, 26•], and NHE3 in the regulation of blood pressure and the development of ANG II-dependent hypertension [27–29, 31••, 32••]. The primary emphases will be on (a) whether ANG II in the proximal tubules of the kidney is derived from local onsite formation or from receptor-mediated uptake of circulating and/or local paracrine ANG II or its substrate angiotensinogen (AGT) and key enzymes renin (and prorenin), (b) whether a functional intracellular ANG II system exists in the proximal tubules of the kidney, and (c) whether NHE3 in the proximal tubules of the kidney plays an important role in the regulation of proximal tubular Na + reabsorption and blood pressure and is required for the development of ANG II-induced hypertension.…”

The importance of the gastrorenal axis in the control of body sodium homeostasis

“…Increased sodium transport in the gastrointestinal tract may contribute to salt sensitivity (Lienhard et al, 2012, Spencer et al, 2014, Li et al, 2015). Gastrin and dopamine can also decrease ion transport in the gastrointestinal tract.…”