Abstract 42: A Novel Role of Proximal Tubular Na+/H+ Exchanger 3 (NHE3) in Angiotensin II-Induced Hypertension in Nhe3-/- Mice with Transgenic Rescue of NHE3 in Intestines

Abstract

The Na +/ H + Exchanger 3 (NHE3) plays an important role in the regulation of Na + and HCO 3 - reabsorption in proximal tubules of the kidney, but its contribution to the renal mechanisms of angiotensin II (ANG II)-induced hypertension remains unknown. Using global NHE3-deficient mice with transgenic rescue of the NHE3 gene in intestines (tg Nhe3 -/- ) as a model of proximal tubule-specific Nhe3 -/- mice, we tested the hypothesis that deletion of NHE3 selectively in proximal tubules impairs long-term blood pressure responses to extracellular and intracellular ANG II. Three groups of wild-type (tg Nhe3 +/+ ) and six groups of tg Nhe3 -/- mice (n=>8 per group) were treated with vehicle, ANG II (40 ng/min, i.p.), or in vivo adenovirus-mediated transfer of an intracellular ANG II fusion protein, ECFP/ANG II, for 2 weeks. Under basal conditions, tgNhe3 -/- mice had significantly lower systolic blood pressure (SBP) (tg Nhe3 +/+ : 119±3 mmHg vs. tg Nhe3 -/- : 109±3 mmHg, p <0.01), glomerular filtration rate (tg Nhe3 +/+ : 148.7±13.0 vs. tg Nhe3 -/- : 83.9±5.1 μl/min, p <0.01), 24 h urine excretion (tg Nhe3 +/+ : 1.25±0.15 vs. tg Nhe3 -/- : 0.68±0.10 ml, p <0.05), 24 h urinary Na + excretion (tg Nhe3 +/+ : 210.5.1±10.3 vs. tg Nhe3 -/- : 36.3±2.3 μmol, p <0.01), and 24 h urinary K + excretion (tg Nhe3 +/+ : 343.8±19.4 vs. tg Nhe3 -/- : 125.5±13.3 μmol, p <0.01). By contrast, basal plasma ANG II (tgNhe3 +/+ : 303.4±26.9 vs. tg Nhe3 -/- : 397.7±27.2 pg/ml, p <0.05), aldosterone (tgNhe3 +/+ : 506±26.3 vs. tg Nhe3 -/- : 759.9±12.7 pg/ml, p <0.01), and the expression of Na + /HCO 3 - cotransporter and Na + /K + -ATPase proteins in proximal tubules ( p <0.01) were significantly increased in tg Nhe3 -/- mice. Deletion of NHE3 selectively in proximal tubules significantly attenuated the SBP responses to exogenous ANG II (tg Nhe3 +/+ : 50±3 vs. tg Nhe3 -/- : 33±5 mmHg, p <0.01) and intracellular ECFP/ANG II (tg Nhe3 +/+ : 18±3 vs. tg Nhe3 -/- : 6±2 mmHg, p <0.01) in tg Nhe3 -/- mice. 24 h urine and urinary Na + excretory responses to ANG II were also attenuated in these mice ( p <0.01), whereas ECFP/ANG II had no further effects on these responses. We concluded that NHE3 in proximal tubules of the kidney is required for maintaining long-term blood pressure responses to extracellular and intracellular ANG II and body salt and fluid homeostasis.