LAUSR

The Na + /H + exchanger 3 (NHE3), a ~85 kDa protein encoded by the SLC9A3 gene, is the most important Na + transporter in the proximal tubules of the kidney. Angiotensin II (ANG II) is well-recognized to increase proximal tubule Na + reabsorption by stimulating NHE3 expression and activity in the proximal tubules. However, a direct cause and effect relationship between ANG II and NHE3 in the proximal tubules in ANG II-induced hypertension has not been determined previously. The present study directly tested the hypothesis that NHE3 in the proximal tubules of the kidney is required for the development of ANG II-induced hypertension using proximal tubule-specific NHE3 knockout mice (PT- Nhe3 -/- ). Specifically, PT- Nhe3 -/- mice were generated using the SGLT2-Cre / Nhe3 loxlox approach, whereas ANG II-induced hypertension was studied in 12 groups (n=5-12 per group) of adult male and female wild-type (WT) and PT- Nhe3 -/- mice. Under basal conditions, systolic (SBP), diastolic (DBP), and mean arterial blood pressure (MAP) were significantly lower in male and female PT- Nhe3 -/- than WT mice ( P <0.01). A high pressor, 1.5 mg/kg/day, i.p., or a slow pressor dose of ANG II, 0.5 mg/kg/day, i.p., for 2 weeks significantly increased SBP, DBP, and MAP in male and female WT mice ( P <0.01), but the hypertensive response to ANG II was markedly attenuated in male and female PT- Nhe3 -/- mice ( P <0.01). ANG II impaired the pressure-natriuresis response in WT mice, whereas proximal tubule-specific deletion of NHE3 improved the pressure-natriuresis response in ANG II-infused PT- Nhe3 -/- mice ( P <0.01). AT 1 receptor blocker losartan completely blocked ANG II-induced hypertension in both WT and PT- Nhe3 -/- mice ( P <0.01). However, inhibition of nitric oxide synthase with L-NAME had no effect on ANG II-induced hypertension in WT or PT- Nhe3 -/- mice (n.s.). Furthermore, ANG II-induced hypertension was significantly attenuated by an orally absorbable NHE3 inhibitor AVE0657. In conclusion, NHE3 in the proximal tubules of the kidney is required for the full development of ANG II-induced hypertension. Our results suggest that NHE3 in the proximal tubules may be therapeutically targeted to treat hypertension induced by ANG II or associated with increased NHE3 expression in the proximal tubules.