| Autor: |
Shuai Shao, Xiao-Dong Li, Yuan-Yuan Lu, Shi-Jin Li, Xiao-Hui Chen, Han-Dan Zhou, Shun He, Yue-Tong Guo, Xiao Lu, Ping-Jin Gao, Ji-Guang Wang, Shao, Shuai, Li, Xiao-Dong, Lu, Yuan-Yuan, Li, Shi-Jin, Chen, Xiao-Hui, Zhou, Han-Dan, He, Shun, Guo, Yue-Tong, Lu, Xiao |
| Zdroj: |
Hypertension (0194911X); Mar2021, Vol. 77 Issue 3, p868-881, 14p |
| Abstrakt: |
Genome-wide association studies have identified that NPR-C (natriuretic peptide receptor-C) variants are associated with elevation of blood pressure. However, the mechanism underlying the relationship between NPR-C and blood pressure regulation remains elusive. Here, we investigate whether NPR-C regulates Ang II (angiotensin II)-induced hypertension through sodium transporters activity. Wild-type mice responded to continuous Ang II infusion with an increased renal NPR-C expression. Global NPR-C deficiency attenuated Ang II-induced increased blood pressure both in male and female mice associated with more diuretic and natriuretic responses to a saline challenge. Interestingly, Ang II increased both total and phosphorylation of NCC (NaCl cotransporter) abundance involving in activation of WNK4 (with-no-lysine kinase 4)/SPAK (Ste20-related proline/alanine-rich kinase) which was blunted by NPR-C deletion. NCC inhibitor, hydrochlorothiazide, failed to induce natriuresis in NPR-C knockout mice. Moreover, low-salt and high-salt diets-induced changes of total and phosphorylation of NCC expression were normalized by NPR-C deletion. Importantly, tubule-specific deletion of NPR-C also attenuated Ang II-induced elevated blood pressure, total and phosphorylation of NCC expression. Mechanistically, in distal convoluted tubule cells, Ang II dose and time-dependently upregulated WNK4/SPAK/NCC kinase pathway and NPR-C/Gi/PLC/PKC signaling pathway mediated NCC activation. These results demonstrate that NPR-C signaling regulates NCC function contributing to sodium retention-mediated elevated blood pressure, which suggests that NPR-C is a promising candidate for the treatment of sodium retention-related hypertension. [ABSTRACT FROM AUTHOR] |
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