Role of Kir4.1/Kir5.1 in mediating Angiotensin-II (Ang-II)-induced stimulation of thiazide-sensitive Na-Cl cotransporter.
| Autor: | Duan XP, Meng XX, Xiao Y, Zhang CB, Gu R, Lin DH, Wang WH |
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| Jazyk: | angličtina |
| Zdroj: | BioRxiv : the preprint server for biology [bioRxiv] 2024 Jul 23. Date of Electronic Publication: 2024 Jul 23. |
| DOI: | 10.1101/2024.07.19.604336 |
| Abstrakt: | Background: Angiotensin-II (Ang-II) perfusion stimulates Kir4.1/Kir5.1 in the distal-convoluted-tubule (DCT) and thiazide-sensitive Na-Cl-cotransporter (NCC). However, the role of Kir4.1/Kir5.1 in mediating the effect of Ang-II on NCC is not understood. Methods: We used immunoblotting and patch-clamp-experiments to examine whether Ang-II-induced stimulation of NCC is achieved by activation of Kir4.1/Kir5.1 of the DCT using kidney-renal-tubule-specific AT1aR-knockout (Ks-AT1aR-KO), Ks-Kir4.1-knockout and the corresponding wild-type mice. Results: Ang-II perfusion for 1, 3 and 7 days progressively increased phosphor-NCC (pNCC) and total-NCC (tNCC) expression and the effect of Ang-II-perfusion on pNCC and tNCC was abolished in Ks-AT1aR-KO. Ang-II perfusion for 1-day robustly stimulates Kir4.1/Kir5.1 in the late DCT (DCT2) and to a lesser degree in the early DCT (DCT1), an effect was absent in Ks-AT1aR-KO mice. However, Ang-II perfusion for 7-days did not further stimulate Kir4.1/Kir5.1 in the DCT2 and only modestly increased Kir4.1/Kir5.1-mediated K + currents in DCT1. Deletion of Kir4.1 not only significantly decreased the expression of pNCC and tNCC but also abolished the effect of 1-day Ang-II perfusion on the expression of phospho-with-no-lysine-kinase-4 (pWNK4), phosphor-ste-20-proline-alanine-rich-kinase (pSPAK), pNCC and tNCC. However, 7-days Ang-II perfusion was still able to significantly stimulate the expression of pSPAK, pWNK4, pNCC and tNCC, and increased thiazide-induced natriuresis in kidney-tubule-specific Kir4.1 knockout (Ks-Kir4.1 KO) mice without obvious changes in K + channel activity in the DCT. Conclusions: Short-term Ang-II induced stimulation of pWNK4, pSPAK and pNCC depends on Kir4.1/Kir5.1 activity. However, long-term Ang-II is able to directly stimulate pWNK4, pSPAK and pNCC by a Kir4.1/Kir5.1 independent mechanism. |
| Databáze: | MEDLINE |
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