Department of Pharmacology of Chinese Materia Medica, Institution of Chinese Integrative Medicine, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, Hebei Province, 050017, China; Department of Pharmacology, Center of Innovative Drug Research and Evaluation, Institute of Medical Science and Health, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, Hebei Province, 050017, China.
Department of Pharmacology, Center of Innovative Drug Research and Evaluation, Institute of Medical Science and Health, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, Hebei Province, 050017, China.
Pharmacol Res. 2021 Feb;164:105391. doi: 10.1016/j.phrs.2020.105391. Epub 2020 Dec 19.
Baroreflex plays a crucial role in regulation of arterial blood pressure (BP). Recently, Piezo1 and Piezo2, the mechanically-activated (MA) ion channels, have been identified as baroreceptors. However, the underlying molecular mechanism for regulating these baroreceptors in hypertension remains unknown. In this study, we used spontaneously hypertensive rats (SHR) and NG-Nitro-l-Arginine (L-NNA)- and Angiotensin II (Ang II)-induced hypertensive model rats to determine the role and mechanism of Piezo1 and Piezo2 in hypertension. We found that Piezo2 was dominantly expressed in baroreceptor nodose ganglia (NG) neurons and aortic nerve endings in Wistar-Kyoto (WKY) rats. The expression of Piezo2 not Piezo1 was significantly downregulated in these regions in SHR and hypertensive model rats. Electrophysiological results showed that the rapidly adapting mechanically-activated (RA-MA) currents and the responsive neuron numbers were significantly reduced in baroreceptor NG neurons in SHR. In WKY rats, the arterial BP was elevated by knocking down the expression of Piezo2 or inhibiting MA channel activity by GsMTx4 in NG. Knockdown of Piezo2 in NG also attenuated the baroreflex and increased serum norepinephrine (NE) concentration in WKY rats. Co-immunoprecipitation experiment suggested that Piezo2 interacted with Neural precursor cell-expressed developmentally downregulated gene 4 type 2 (Nedd4-2, also known as Nedd4L); Electrophysiological results showed that Nedd4-2 inhibited Piezo2 MA currents in co-expressed HEK293T cells. Additionally, Nedd4-2 was upregulated in NG baroreceptor neurons in SHR. Collectively, our results demonstrate that Piezo2 not Piezo1 may act as baroreceptor to regulate arterial BP in rats. Nedd4-2 induced downregulation of Piezo2 in baroreceptor NG neurons leads to hypertension in rats. Our findings provide a novel insight into the molecular mechanism for the regulation of baroreceptor Piezo2 and its critical role in the pathogenesis of hypertension.
压力感受反射在调节动脉血压（BP）中起着至关重要的作用。最近，Piezo1 和 Piezo2，即机械激活（MA）离子通道，已被鉴定为压力感受器。然而，高血压中调节这些压力感受器的潜在分子机制尚不清楚。在这项研究中，我们使用自发性高血压大鼠（SHR）和 NG-硝基-L-精氨酸（L-NNA）和血管紧张素 II（Ang II）诱导的高血压模型大鼠来确定 Piezo1 和 Piezo2 在高血压中的作用和机制。我们发现 Piezo2 在 Wistar-Kyoto（WKY）大鼠的压力感受器迷走神经节（NG）神经元和主动脉神经末梢中表达占主导地位。在 SHR 和高血压模型大鼠的这些区域中，Piezo2 的表达而非 Piezo1 的表达显著下调。电生理结果表明，在 SHR 的压力感受器 NG 神经元中，快速适应机械激活（RA-MA）电流和响应神经元数量显著减少。在 WKY 大鼠中，通过敲低 NG 中的 Piezo2 表达或抑制 MA 通道活性来抑制 GsMTx4，动脉血压升高。在 WKY 大鼠中，NG 中的 Piezo2 敲低也减弱了压力反射，并增加了血清去甲肾上腺素（NE）浓度。共免疫沉淀实验表明 Piezo2 与 Neural precursor cell-expressed developmentally downregulated gene 4 type 2（Nedd4-2，也称为 Nedd4L）相互作用；电生理结果表明，Nedd4-2 在共表达的 HEK293T 细胞中抑制 Piezo2 MA 电流。此外，在 SHR 的 NG 压力感受器神经元中，Nedd4-2 上调。总的来说，我们的结果表明，Piezo2 而非 Piezo1 可能作为压力感受器调节大鼠的动脉血压。Nedd4-2 在 NG 压力感受器神经元中诱导 Piezo2 的下调导致大鼠高血压。我们的发现为压力感受器 Piezo2 的调节分子机制及其在高血压发病机制中的关键作用提供了新的见解。
