Atrial Natriuretic Peptide Promotes Neurite Outgrowth and Survival of Cochlear Spiral Ganglion Neurons in vitro Through NPR-A/cGMP/PKG Signaling.
Atrial Natriuretic Peptide Promotes Neurite Outgrowth and Survival of Cochlear Spiral Ganglion Neurons in vitro Through NPR-A/cGMP/PKG Signaling.
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DOI：
10.3389/fcell.2021.681421
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发表时间：
2021
影响因子：
5.5
通讯作者：
Zha DJ
中科院分区：
文献类型：
--
作者：
Sun F;Zhou K;Tian KY;Zhang XY;Liu W;Wang J;Zhong CP;Qiu JH;Zha DJ
感音神经性听力损失（SNHL）是影响地球仪周围数百万人的主要公共卫生问题，其与耳蜗内的毛细胞和螺旋神经节神经元（SGN）的不可逆退化相关。使用调节神经突再生和神经元存活的生物活性分子来重建听觉上皮或植入电极与SGN神经突之间的连接的策略将成为SNHL的有吸引力的治疗候选者。作为细胞内的第二信使，环鸟苷-3 '，5'-单磷酸（cGMP）可以通过利钠肽激活颗粒鸟苷酸环化酶偶联的利钠肽受体（NPR）来合成，其进而调节神经元功能的多个方面，包括神经元发育和神经元存活。心房钠尿肽（ANP）及其特异性受体（NPR-A和NPR-C）是一种心源性激素，广泛表达于神经系统，可能参与多种神经功能的维持。尽管以往的文献和我们的报告表明，ANP及其受体的存在于内耳，特别是在螺旋神经节，其潜在的调节机制的听觉神经元的功能特性仍然不完全了解。我们最近发表的研究表明，ANP可以通过激活NPR-A/cGMP/PKG级联反应以剂量依赖的方式促进SGN的轴突生长。在本研究中，ANP及其受体介导的下游信号通路的影响，神经突起的生长，神经突起的吸引力，和神经元存活的SGNs在体外评估采用培养的器官型外植体和分离的神经元从出生后的大鼠。我们的数据表明，ANP可以支持和吸引SGN的轴突生长，并通过触发NPR-A/cGMP/PKG通路，具有提高SGN对谷氨酸诱导的兴奋性毒性的神经元存活的高能力。ANP/NPRA/cGMP/PKG依赖性信号对SGN的神经再生和神经保护作用将代表听力损伤的有吸引力的治疗候选者。
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.
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