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Genetic Deletion of AT Receptor or Na/H Exchanger 3 Selectively in the Proximal Tubules of the Kidney Attenuates Two-Kidney, One-Clip Goldblatt Hypertension in Mice

International Journal of Molecular Sciences, ISSN: 1422-0067, Vol: 23, Issue: 24
2022
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Article Description

The roles of angiotensin II (Ang II) AT (AT) receptors and its downstream target Na/H exchanger 3 (NHE3) in the proximal tubules in the development of two-kidney, 1-clip (2K1C) Goldblatt hypertension have not been investigated previously. The present study tested the hypothesis that deletion of the AT receptor or NHE3 selectively in the proximal tubules of the kidney attenuates the development of 2K1C hypertension using novel mouse models with proximal tubule-specific deletion of AT receptors or NHE3. 2K1C Goldblatt hypertension was induced by placing a silver clip (0.12 mm) on the left renal artery for 4 weeks in adult male wild-type (WT), global Agtr1a, proximal tubule (PT)-specific PT-Agtr1a or PT-Nhe3 mice, respectively. As expected, telemetry blood pressure increased in a time-dependent manner in WT mice, reaching a maximal response by Week 3 (p < 0.01). 2K1C hypertension in WT mice was associated with increases in renin expression in the clipped kidney and decreases in the nonclipped kidney (p < 0.05). Plasma and kidney Ang II were significantly increased in WT mice with 2K1C hypertension (p < 0.05). Tubulointerstitial fibrotic responses were significantly increased in the clipped kidney (p < 0.01). Whole-body deletion of AT receptors completely blocked the development of 2K1C hypertension in Agtr1a mice (p < 0.01 vs. WT). Likewise, proximal tubule-specific deletion of Agtr1a in PT-Agtr1a mice or NHE3 in PT-Nhe3 mice also blocked the development of 2K1C hypertension (p < 0.01 vs. WT). Taken together, the present study provides new evidence for a critical role of proximal tubule Ang II/AT (AT)/NHE3 axis in the development of 2K1C Goldblatt hypertension.

Bibliographic Details

Li, Xiao Chun; Hassan, Rumana; Leite, Ana Paula O; Katsurada, Akemi; Dugas, Courtney; Sato, Ryosuke; Zhuo, Jia Long

MDPI AG

Chemical Engineering; Biochemistry, Genetics and Molecular Biology; Chemistry; Computer Science

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