From the Department of Cardiovascular Medicine, Department of Hypertension, Ruijin Hospital and State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, China.
Hypertension. 2021 Mar 3;77(3):868-881. doi: 10.1161/HYPERTENSIONAHA.120.15636. Epub 2021 Jan 25.
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.
全基因组关联研究表明，NPR-C（利钠肽受体-C）变体与血压升高有关。然而，NPR-C 与血压调节之间的关系的机制仍不清楚。在这里，我们研究了 NPR-C 是否通过钠转运体活性调节 Ang II（血管紧张素 II）诱导的高血压。野生型小鼠对持续的 Ang II 输注反应是肾 NPR-C 表达增加。NPR-C 全身性缺失减弱了雄性和雌性小鼠的 Ang II 诱导的血压升高，同时对盐水挑战的利尿和利钠反应增加。有趣的是，Ang II 增加了总 NCC（NaCl 共转运蛋白）和磷酸化的含量，涉及 WNK4（无赖氨酸激酶 4）/SPAK（Ste20 相关脯氨酸/丙氨酸丰富激酶）的激活，这被 NPR-C 缺失所抑制。NCC 抑制剂氢氯噻嗪在 NPR-C 敲除小鼠中未能诱导利钠作用。此外，NPR-C 缺失使低盐和高盐饮食诱导的 NCC 表达的总变化和磷酸化正常化。重要的是，管腔特异性的 NPR-C 缺失也减弱了 Ang II 诱导的血压升高、总 NCC 和磷酸化的表达。从机制上讲，在远曲小管细胞中，Ang II 剂量和时间依赖性地上调了 WNK4/SPAK/NCC 激酶途径和 NPR-C/Gi/PLC/PKC 信号转导途径介导的 NCC 激活。这些结果表明，NPR-C 信号调节 NCC 功能，导致钠潴留介导的血压升高，这表明 NPR-C 是治疗钠潴留相关高血压的有前途的候选药物。
