MANP Activation Of The cGMP Inhibits Aldosterone Via PDE2 And CYP11B2 In H295R Cells And In Mice.
MANP Activation Of The cGMP Inhibits Aldosterone Via PDE2 And CYP11B2 In H295R Cells And In Mice.
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DOI：
10.1161/hypertensionaha.121.18906
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发表时间：
2022-08
期刊：
影响因子：
8.3
通讯作者：
Burnett, John C., Jr.
中科院分区：
文献类型：
--
作者：
Chen, Yang;Iyer, Seethalakshmi R.;Nikolaev, Viacheslav O.;Naro, Fabio;Pellegrini, Manuela;Cardarelli, Silvia;Ma, Xiao;Lee, Hon-Chi;Burnett, John C., Jr.
醛固酮是心脏和肾脏疾病的关键病理驱动因素。我们最近发现，MANP是一种新的心钠素类似物，在体内具有比ANP更强的醛固酮抑制作用。MANP和NP增强疗法萨舒比利/valsartan正在研究中，用于治疗人类高血压。了解利钠肽(NPs)抑制醛固酮的机制仍是当务之急。关于颗粒鸟苷酸环化酶A受体(PGC-A)和NP清除受体(NPRC)在醛固酮抑制中的作用，报道了相互矛盾的结果。此外，蛋白激酶G(PKG)和磷酸二酯酶(PDE)在醛固酮调节中的作用尚不清楚。在本研究中，我们研究了醛固酮在人肾上腺皮质细胞系H295R和小鼠体内调节的分子机制。我们首先提供的证据表明，PGC-A，而不是NPRC，介导了醛固酮抑制。接下来，我们通过特定的激动剂、拮抗剂、siRNA沉默和荧光共振能量转移(FRET)实验证实了MANP通过PDE2而不是PKG抑制醛固酮。此外，这种抑制作用是通过降低细胞内钙离子水平来实现的。然后，我们证明了MANP通过PDE2直接降低了醛固酮合成酶CYP11B2的表达。最后，在PDE2基因敲除小鼠中，与体外研究结果一致，胚胎肾上腺细胞色素P11B2显著增加。我们的结果创新性地探索和扩展了NP/PGC-A/cGMP/PDE2途径在体内外对MANP抑制醛固酮的作用。此外，我们的数据也支持MANP作为一种治疗醛固酮过剩的新型ANP类似药物的开发。
Aldosterone is a critical pathological driver for cardiac and renal disease. We recently discovered that MANP, a novel atrial natriuretic peptide (ANP) analog, possessed more potent aldosterone inhibitory action than ANP in vivo. MANP and NP-augmenting therapy sacubitril/valsartan are under investigations for human hypertension treatment. Understanding the elusive mechanism of aldosterone inhibition by natriuretic peptides (NPs) remains to be a priority. Conflicting results were reported on the roles of the particulate guanylyl cyclase A receptor (pGC-A) and NP clearance receptor (NPRC) in aldosterone inhibition. Furthermore, the function of protein kinase G (PKG) and phosphodiesterases (PDE) on aldosterone regulation are not clear. In the present study, we investigated the molecular mechanism of aldosterone regulation in a human adrenocortical cell line H295R and in mice. We first provided evidence to show that pGC-A, not NPRC, mediates aldosterone inhibition. Next, we confirmed that MANP inhibits aldosterone via PDE2 not PKG, with specific agonists, antagonists, siRNA silencing, and fluorescence resonance energy transfer (FRET) experiments. Further, the inhibitory effect is mediated by a reduction of intracellular Ca2+ levels. We then illustrated that MANP directly reduces aldosterone synthase CYP11B2 expression via PDE2. Lastly, in PDE2 knockout mice, consistent with in vitro findings, embryonic adrenal CYP11B2 is markedly increased. Our results innovatively explore and expand the NP/pGC-A/cGMP/PDE2 pathway for aldosterone inhibition by MANP in vitro and in vivo. Additionally, our data also support the development of MANP as a novel ANP analog drug for aldosterone excess treatment.