Proximal Tubule-Specific Deletion of the NHE3 (Na + /H + Exchanger 3) in the Kidney Attenuates Ang II (Angiotensin II)-Induced Hypertension in Mice

Author:

Li Xiao C.12,Zhu Dongmin13,Chen Xu1,Zheng Xiaowen14,Zhao Chunling14,Zhang Jianfeng14,Soleimani Manoocher5,Rubera Isabelle6,Tauc Michel6,Zhou Xinchun7,Zhuo Jia L.12

Affiliation:

1. From the Department of Pharmacology and Toxicology (X.C.L., D.Z., X.C., X. Zheng, C.Z., J.Z., J.L.Z.), University of Mississippi Medical Center, Jackson

2. Division of Nephrology, Department of Medicine (X.C.L., J.L.Z.), University of Mississippi Medical Center, Jackson

3. Department of Anesthesiology, Shenzhen Far East Obstetrics and Gynecology Hospital, China (D.Z.)

4. Department of Emergency Medicine, Second Affiliated Hospital, Guangxi Medical University, Nanning, China (X. Zheng, C.Z., J.Z.)

5. Division of Nephrology and Hypertension, Department of Internal Medicine, The University of Cincinnati College of Medicine, OH (M.S.)

6. Laboratoire de Physiomédecine Moléculaire, LP2M, UMR-CNRS 7370, Université Côte d’Azur, Nice Cedex 2, France (I.R., M.T.).

7. Department of Pathology (X. Zhou), University of Mississippi Medical Center, Jackson

Abstract

The present study directly tested the hypothesis that the NHE3 (Na + /H + exchanger 3) in the proximal tubules of the kidney is required for the development of Ang II (angiotensin II)-induced hypertension using PT- Nhe3 −/− (proximal tubule-specific NHE3 knockout) mice. 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 blood pressure, diastolic blood pressure, and mean arterial blood pressure were significantly lower in male and female PT- Nhe3 −/− than WT mice ( P <0.01). A high pressor, 1.5 mg/kg per day, intraperitoneal or a slow pressor dose of Ang II, 0.5 mg/kg per day, intraperitoneal for 2 weeks significantly increased systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure 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-N G -Nitroarginine methyl ester had no effect on Ang II-induced hypertension in WT or PT- Nhe3 −/− mice (not significant). 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 may be a therapeutical target in hypertension induced by Ang II or with increased NHE3 expression in the proximal tubules.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Internal Medicine

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