Piezo2 channel in nodose ganglia neurons is essential in controlling hypertension in a pathway regulated directly by Nedd4-2

Lifang Huo; Yiting Gao; Dongfang Zhang; Shengnan Wang; Yu Han; Hongchao Men; Zuxiao Yang; Xia Qin; Ri Wang; Dezhi Kong; Hui Bai; Hailin Zhang; Wei Zhang; Zhanfeng Jia

doi:10.1016/j.phrs.2020.105391

Piezo2 channel in nodose ganglia neurons is essential in controlling hypertension in a pathway regulated directly by Nedd4-2

Pharmacol Res. 2021 Feb:164:105391. doi: 10.1016/j.phrs.2020.105391. Epub 2020 Dec 19.

Authors

Lifang Huo¹, Yiting Gao², Dongfang Zhang², Shengnan Wang², Yu Han³, Hongchao Men², Zuxiao Yang⁴, Xia Qin⁴, Ri Wang⁴, Dezhi Kong⁴, Hui Bai⁵, Hailin Zhang², Wei Zhang⁶, Zhanfeng Jia⁷

Affiliations

¹ 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.
² 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.
³ 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 Pharmacy, Children's Hospital of Hebei Province, China.
⁴ 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.
⁵ Department of Cardiac Ultrasound, The Second Hospital of Hebei Medical University, China.
⁶ 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. Electronic address: weizhang@hebmu.edu.cn.
⁷ 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. Electronic address: jiazf@hebmu.edu.cn.

PMID: 33352230
DOI: 10.1016/j.phrs.2020.105391

Abstract

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.

Keywords: Ang II (PubChem CID: 172198); Baroreceptor; Baroreflex; Benzylpenicillin (PubChem CID: 5904); GsMTx4 (PubChem CID: 146018896); Hypertension; Isoflurane (PubChem CID: 3763); L-NNA (PubChem CID: 440005); Nedd4-2; Nodose ganglia; PE (PubChem CID: 6041); Pentobarbital sodium (PubChem CID: 23676152); Piezo channel; Yoda1 (PubChem CID: 2746822).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Aorta, Thoracic / innervation
Baroreflex
Cells, Cultured
Humans
Hypertension / physiopathology*
Ion Channels / physiology*
Male
Nedd4 Ubiquitin Protein Ligases / physiology*
Neurons / physiology*
Nodose Ganglion / physiology*
Pressoreceptors / physiology*
Rats
Rats, Inbred SHR
Rats, Inbred WKY
Signal Transduction

Substances

Ion Channels
PIEZO2 protein, human
piezo2 protein, rat
Nedd4 Ubiquitin Protein Ligases