腎臓における近位尿細管特異的なNHE3（Na/H交換体3）の欠失は、マウスのAng II（アンジオテンシンII）誘発性高血圧を減衰させる

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

• Xiao C Li
• Dongmin Zhu
• Xu Chen
• Xiaowen Zheng
• Chunling Zhao
• Jianfeng Zhang
• Manoocher Soleimani
• Isabelle Rubera
• Michel Tauc
• Xinchun Zhou
• Jia L Zhuo

抄録

本研究では、PT-Nhe3（近位尿細管特異的NHE3ノックアウト）マウスを用いて、腎臓の近位尿細管に存在するNHE3（Na/H交換体3）がAng II（アンジオテンシンII）誘発性高血圧の発症に必要であるという仮説を直接検証した。具体的には、PT-Nhe3マウスをSGLT2-Cre/Nhe3アプローチで作製し、野生型（WT）マウスとPT-Nhe3マウスの成体雄雌12群（各群n=5〜12）でAng II誘導性高血圧を検討した。基底条件では、収縮期血圧、拡張期血圧、平均動脈血圧はWTマウスに比べて雄雌のPT-Nhe3マウスで有意に低かった（P＜0.01）。高圧、1.5mg/kg/日、腹腔内投与または遅圧、0.5mg/kg/日、腹腔内投与のAng IIを2週間投与すると、雄雌WTマウスでは収縮期血圧、拡張期血圧、平均動脈圧が有意に上昇したが（P<0.01）、雄雌PT-Nhe3マウスではAng IIに対する高血圧反応が著しく減衰した（P<0.01）。一方、近位尿細管特異的にNHE3を欠失させたPT-Nhe3マウスでは、Ang IIを投与したPT-Nhe3マウスでは血圧-ナトリウム利尿反応が改善された(P<0.01)。AT受容体遮断薬ロサルタンはWTマウスとPT-Nhe3マウスの両方でAng II誘発性高血圧を完全に遮断した(P<0.01)。しかし、L-N-ニトロアルギニンメチルエステルによる一酸化窒素合成酵素の阻害は、WTマウスおよびPT-Nhe3マウスのAng II誘導性高血圧に影響を与えなかった(有意ではなかった)。さらに、経口吸収性のNHE3阻害剤AVE0657により、Ang II誘導性高血圧は有意に抑制された。結論として、腎臓の近位尿細管内のNHE3は、Ang IIによって誘発された高血圧症、または近位尿細管内のNHE3発現が増加した高血圧症の治療標的となる可能性がある。

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 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 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-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.