Atrial Natriuretic Peptide Promotes Neurite Outgrowth and Survival of Cochlear Spiral Ganglion Neurons in vitro Through NPR-A/cGMP/PKG Signaling

Fei Sun; Ke Zhou; Ke-Yong Tian; Xin-Yu Zhang; Wei Liu; Jie Wang; Cui-Ping Zhong; Jian-Hua Qiu; Ding-Jun Zha

doi:10.3389/fcell.2021.681421

Atrial Natriuretic Peptide Promotes Neurite Outgrowth and Survival of Cochlear Spiral Ganglion Neurons in vitro Through NPR-A/cGMP/PKG Signaling

Front Cell Dev Biol. 2021 Jun 23:9:681421. doi: 10.3389/fcell.2021.681421. eCollection 2021.

Authors

Fei Sun¹, Ke Zhou², Ke-Yong Tian¹, Xin-Yu Zhang¹, Wei Liu¹, Jie Wang³, Cui-Ping Zhong⁴, Jian-Hua Qiu¹, Ding-Jun Zha¹

Affiliations

¹ Department of Otolaryngology-Head and Neck Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
² Department of Laboratory Medicine, Institute of Clinical Laboratory Medicine of PLA, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
³ Department of Otolaryngology-Head and Neck Surgery, The Affiliated Children Hospital of Xi'an Jiaotong University, Xi'an, China.
⁴ Department of Otolaryngology-Head and Neck Surgery, The 940th Hospital of Joint Logistics Support Force of PLA, Lanzhou, China.

Abstract

Sensorineural hearing loss (SNHL) is a dominant public health issue affecting millions of people around the globe, which is correlated with the irreversible deterioration of the hair cells and spiral ganglion neurons (SGNs) within the cochlea. Strategies using bioactive molecules that regulate neurite regeneration and neuronal survival to reestablish connections between auditory epithelium or implanted electrodes and SGN neurites would become attractive therapeutic candidates for SNHL. As an intracellular second messenger, cyclic guanosine-3',5'-monophosphate (cGMP) can be synthesized through activation of particulate guanylate cyclase-coupled natriuretic peptide receptors (NPRs) by natriuretic peptides, which in turn modulates multiple aspects of neuronal functions including neuronal development and neuronal survival. As a cardiac-derived hormone, atrial natriuretic peptide (ANP), and its specific receptors (NPR-A and NPR-C) are broadly expressed in the nervous system where they might be involved in the maintenance of diverse neural functions. Despite former literatures and our reports indicating the existence of ANP and its receptors within the inner ear, particularly in the spiral ganglion, their potential regulatory mechanisms underlying functional properties of auditory neurons are still incompletely understood. Our recently published investigation revealed that ANP could promote the neurite outgrowth of SGNs by activating NPR-A/cGMP/PKG cascade in a dose-dependent manner. In the present research, the influence of ANP and its receptor-mediated downstream signaling pathways on neurite outgrowth, neurite attraction, and neuronal survival of SGNs in vitro was evaluated by employing cultures of organotypic explant and dissociated neuron from postnatal rats. Our data indicated that ANP could support and attract neurite outgrowth of SGNs and possess a high capacity to improve neuronal survival of SGNs against glutamate-induced excitotoxicity by triggering the NPR-A/cGMP/PKG pathway. The neuroregenerative and neuroprotective effects of ANP/NPRA/cGMP/PKG-dependent signaling on SGNs would represent an attractive therapeutic candidate for hearing impairment.

Keywords: atrial natriuretic peptide; cGMP; natriuretic peptide receptors; neurite outgrowth; neuroprotection; sensorineural hearing loss; spiral ganglion neuron.