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Genetic Evidence for A Critical Role of Intratubular Angiotensin II AT 1a Receptors in The Proximal Tubules of The Kidney in Two‐Kidney, One‐Clip Goldblatt Hypertension in PT‐ Agtr1a ‐/‐ Mice
Author(s) -
Li Xiao C.,
Hassan Rumana,
Leite Ana P. O.,
Dugas Courtney,
Sato Ryosuke,
Sato Akemi,
Zhuo Jia L.
Publication year - 2022
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2022.36.s1.r4637
Subject(s) - angiotensin ii receptor type 1 , renin–angiotensin system , medicine , endocrinology , kidney , angiotensin ii , receptor , sodium–hydrogen antiporter , blood pressure , renovascular hypertension , chemistry , biology , sodium , organic chemistry
It was previously reported the activation of the renin‐angiotensin system (RAS) in the clipped kidney plays a critical role in the development of two‐kidney, one‐clip Goldblatt hypertension (2K1C). However, most of previous studies used the global angiotensin II (Ang II) type 1a (AT 1a ) receptor ( Agtr1a ‐/‐ ) knockout model or used systemic AT 1 receptor blockers (ARB) to determine renal mechanisms of 2K1C hypertension. The roles of intratubular AT 1 (AT 1a ) receptors or its downstream target Na + /H + exchanger 3 (NHE3) in the proximal tubules in the development of 2K1C hypertension has not been determined previously. In the present study, we tested the hypothesis that genetic deletion of AT 1 (AT 1a ) receptors selectively in the proximal tubules attenuates the development of 2K1C hypertension via AT 1 (AT 1a ) receptor‐mediated, Na + /H + exchanger 3 (NHE3)‐dependent mechanisms. To test the hypothesis, 2K1C Goldblatt hypertension was induced by placing a silver clip, 0.12 mm internal diameter, 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 ‐/‐ (Na + /H + exchanger 3) mice, respectively. As expected, systolic blood pressure increased in a time‐dependent manner in wild‐type mice, reaching a maximal response by Week 3 (Basal: 112 ± 2 vs. 2K1C: 149 ± 4 mmHg, n=12, P <0.01). 2K1C hypertension in WT mice was associated with increases in renin mRNA expression in the clipped kidney (Control: 2066 ± 255 vs. Clipped: 3144 ± 569 copies/ng RNA, P <0.01), and decreases in renin mRNA expression in the nonclipped right kidney (1738 ± 341 copies/ng RNA, P <0.05). Plasma Ang II levels were significantly increased in WT mice with 2K1C hypertension (Control: 50.2 ± 7.2 vs. 2K1C: 109.7 ± 17.2 pg/ml, P <0.05). Glomerular and tubulointerstitial fibrotic responses were also significantly increased in the clipped kidney ( P <0.01). By comparisons, the development of 2K1C hypertension was entirely prevented in Agtr1a ‐/‐ (Basal: 88 ± 4 vs. 2K1C: 92 ± 2 mmHg, n=9, n.s .), or significantly attenuated in PT‐ Agtr1a ‐/‐ mice (Basal: 101 ± 2 vs. 2K1C: 104 ± 4 mmHg, n=12, n.s .) or in PT‐ Nhe3 ‐/‐ mice (Basal: 103 ± 3 vs. 109 ± 5 mmHg, n.s .). Renin mRNA expression was not different in clipped and nonclipped kidney of Agtr1a ‐/‐ mice, but it was decreased in the nonclipped kidney of PT‐ Agtr1a ‐/‐ mice ( P <0.05). Furthermore, glomerular and tubulointerstitial fibrotic responses were also markedly attenuated in the clipped kidney in PT‐ Agtr1a ‐/‐ mice ( P <0.05). We conclude that the results of the present study provide strong evidence for a critical role of AT 1a receptors and NHE3 in the proximal tubules of the kidney in the development of 2K1C Goldblatt hypertension in mice.