Role of Angiotensin II Type 1a Receptor (AT1aR) of Renal Tubules in Regulating Inwardly Rectifying Potassium Channels 4.2 (Kir4.2), Kir4.1, and Epithelial Na+Channel (Enac)

Authors

Xin Peng Duan, Xuzhou Medical University
Yu Xiao, Qiqihar Medical College
Xiao Tong Su, OHSU School of Medicine
Jun Ya Zheng, New York Medical College
Susan Gurley, OHSU School of Medicine
Jacqueline Emathinger, OHSU School of Medicine
Chao Ling Yang, OHSU School of Medicine
James McCormick, OHSU School of Medicine
David H. Ellison, OHSU School of Medicine
Dao Hong Lin, New York Medical College
Wen Hui Wang, New York Medical College

Author Type(s)

Faculty

DOI

10.1161/HYPERTENSIONAHA.123.21389

Journal Title

Hypertension

First Page

126

Last Page

137

Document Type

Article

Publication Date

1-1-2024

Department

Pharmacology

Keywords

amiloride, angiotensin II, genotype, knockout mice, perfusion

Disciplines

Medicine and Health Sciences

Abstract

BACKGROUND: Kir4.2 and Kir4.1 play a role in regulating membrane transport in the proximal tubule (PT) and in the distal-convoluted-tubule (DCT), respectively. METHODS: We generated kidney-tubule-specific-AT1aR-knockout (Ks-AT1aR-KO) mice to examine whether renal AT1aR regulates Kir4.2 and Kir4.1. RESULTS: Ks-AT1aR-KO mice had a lower systolic blood pressure than Agtr1a^flox/flox(control) mice. Ks-AT1aR-KO mice had a lower expression of NHE3(Na⁺/H⁺-exchanger 3) and Kir4.2, a major Kir-channel in PT, than Agtr1a^flox/floxmice. Whole-cell recording also demonstrated that the membrane potential in PT of Ks-AT1aR-KO mice was lesser negative than Agtr1a^flox/floxmice. The expression of Kir4.1 and Kir5.1, Kir4.1/Kir5.1-mediated K⁺currents of DCT and DCT membrane potential in Ks-AT1aR-KO mice, were similar to Agtr1a^flox/floxmice. However, angiotensin II perfusion for 7 days hyperpolarized the membrane potential in PT and DCT of the control mice but not in Ks-AT1aR-KO mice, while angiotensin II perfusion did not change the expression of Kir4.1, Kir4.2, and Kir5.1. Deletion of AT1aR did not significantly affect the expression of αENaC (epithelial Na⁺channel) and βENaC but increased cleaved γENaC expression. Patch-clamp experiments demonstrated that deletion of AT1aR increased amiloride-sensitive Na⁺-currents in the cortical-collecting duct but not in late-DCT. However, tertiapin-Q sensitive renal outer medullary potassium channel currents were similar in both genotypes. CONCLUSIONS: AT1aR determines the baseline membrane potential of PT by controlling Kir4.2 expression/activity but AT1aR is not required for determining the baseline membrane potential of the DCT and Kir4.1/Kir5.1 activity/expression. However, AT1aR is required for angiotensin II-induced hyperpolarization of basolateral membrane of PT and DCT. Deletion of AT1aR had no effect on baseline renal outer medullary potassium channel activity but increased ENaC activity in the CCD.

Recommended Citation

Duan, X., Xiao, Y., Su, X., Zheng, J., Gurley, S., Emathinger, J., Yang, C., McCormick, J., Ellison, D., Lin, D., & Wang, W. (2024). Role of Angiotensin II Type 1a Receptor (AT1aR) of Renal Tubules in Regulating Inwardly Rectifying Potassium Channels 4.2 (Kir4.2), Kir4.1, and Epithelial Na+Channel (Enac). Hypertension, 81 (1), 126-137. https://doi.org/10.1161/HYPERTENSIONAHA.123.21389