Piezo2 channel in nodose ganglia neurons is essential in controlling hypertension in a pathway regulated directly by Nedd4-2. (February 2021)

• Record Type: Journal Article
• Authors: Huo, Lifang; Gao, Yiting; Zhang, Dongfang; Wang, Shengnan; Han, Yu; Men, Hongchao; Yang, Zuxiao; Qin, Xia; Wang, Ri; Kong, Dezhi; Bai, Hui; Zhang, Hailin; Zhang, Wei; Jia, Zhanfeng
• Is Part Of: Pharmacological research. Volume 164(2021)
• Publication Date: 2021-02
• Subjects: Ang II (PubChem CID: 172198) -- L-NNA (PubChem CID: 440005) -- GsMTx4 (PubChem CID: 146018896) -- Yoda1 (PubChem CID: 2746822) -- PE (PubChem CID: 6041) -- Isoflurane (PubChem CID: 3763) -- Pentobarbital sodium (PubChem CID: 23676152) -- Benzylpenicillin (PubChem CID: 5904); BP blood pressure -- SBP systolic blood pressure -- DBP diastolic blood pressure -- MAP mean arterial pressure -- PP pulse pressure -- MA mechanically-activated -- RA-MA rapidly adapting type of mechanically-activated -- IA intermediately adapting -- SA slowly adapting -- NG nodose ganglia -- SHR spontaneously hypertensive rat -- WKY Wistar-Kyoto -- L-NNA NG-Nitro-l-Arginine -- shRNA short hairpin RNA -- Nedd4-2 (Nedd4L) neural precursor cell-expressed developmentally downregulated gene 4 type 2 -- nNOS neuronal isoform of nitric oxide synthase -- Ang II Angiotensin II -- GsMTx4 M-theraphotoxin-Gr1a -- HR heart rate -- γENaC epithelial sodium channel γ subunit -- ASIC2 acid-sensing ion channel 2 -- TRPC5 transient receptor potential cation channel classical subtype 5 -- SP-DiO 3, 3′-Dioctadecyl-5, 5′-Di(4-Sulfophenyl) Oxacarbocyanine sodium salt -- DiI 1, 1′-dioleyl-3, 3, 3′, 3′-tetramethylindo-carbocyanine methane sulfonate -- NE norepinephrine -- PE Phenylephrine -- IF immunofluorescence -- NR non-responsive; Hypertension -- Baroreceptor -- Piezo channel -- Nedd4-2 -- Baroreflex -- Nodose ganglia; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2020.105391
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Highlights: Mechanically-activated Piezo2 channel was highly expressed in baroreceptor nodose ganglia (NG) neurons as well as aortic nerve terminals in normotensive rats and significantly downregulated in hypertensive rats. Downregulation of Piezo2 in NG impaired the baroreflex and induced hypertension in rats. Nedd4-2 was involved in the downregulation of Piezo2 in NG in hypertensive rats. In the future, targeting Piezo2 could be a new strategy in the treatment of hypertension. 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.