Spironolactone inhibits endothelial-mesenchymal transition via the adenosine A2A receptor to reduce cardiorenal fibrosis in rats
Spironolactone inhibits endothelial-mesenchymal transition via the adenosine A2A receptor to reduce cardiorenal fibrosis in rats
复制标题
螺内酯通过腺苷 A2A 受体抑制内皮间质转化，减轻大鼠心肾纤维化
DOI：
10.1016/j.lfs.2019.01.017
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发表时间：
2019-05-01
期刊：
影响因子：
6.1
通讯作者：
Zhou, Hao
中科院分区：
文献类型：
--
作者：
Chen, Xingxing;Ge, Wenhua;Zhou, Hao
目的：心肾综合征的发病机制复杂且尚未完全了解；纤维化似乎是这些疾病病理生理学的主要驱动力。螺内酯可通过抑制血管内皮细胞间充质转化(EndMT)来减轻心脏或肾脏纤维化。螺内酯的保护作用可能依赖于腺苷受体的激活，但腺苷A2a受体(A2AR)的作用尚不清楚。我们推测螺内酯可能通过调节A2AR来抑制EndMT，减少心肾重构。主要方法：皮下注射异丙肾上腺素(Iso)建立大鼠肾损伤心力衰竭模型。评估心、肾功能、纤维化、EndMT标志物、腺苷和A2AR的表达。用转化生长因子-β诱导原代培养的人脐静脉内皮细胞(HUVECs)发生EndMT。将大鼠或细胞分为四组：单独使用螺内酯或联合使用A2AR拮抗剂ZM241385或两者都不使用的组，并与正常对照组进行比较。主要发现：异丙肾上腺素处理的大鼠出现心脏和肾脏纤维化，心肾功能受损，EndMT增强，A2AR表达降低。螺内酯在体内和体外均显著上调A2AR的表达，抑制EndMT的表达。此外，螺内酯改善了心肾重塑，减少了功能障碍。这些变化因服用ZM241385而加剧。综上所述，这些发现表明螺内酯上调A2AR以减少EndMT和改善心肾纤维化。意义：螺内酯的抗纤维化作用可能部分依赖于A2AR的上调，A2AR可能是治疗心肾综合征的潜在靶点。
Aims: The mechanisms underlying cardiorenal syndromes are complex and not fully understood; Fibrosis seems to be a primary driver of the diseases' pathophysiology. Spironolactone can reduce cardiac or renal fibrosis by inhibiting endothelial-mesenchymal transition (EndMT). Spironolactone protection may rely on activation of adenosine receptors, but the role of the adenosine A2A receptor (A2AR) is unclear. We hypothesize that spironolactone may modulate A2AR to suppress EndMT and reduce cardiorenal remodeling.Main methods: A model of renal injury followed by heart failure was established by subcutaneous administration of isoprenaline (Iso) to rats. Assessment of cardiac and renal function, fibrosis, EndMT markers, adenosine and A2AR expression was performed. TGF-beta was used to induce EndMT in primary human umbilical vein endothelial cells (HUVECs). Rats or cells were divided into four groups: those that treated with spironolactone alone or in combination with A2AR antagonist ZM241385 or neither, and compared to normal controls.Key findings: Isoprenaline-treated rats exhibited cardiac and renal fibrosis, impaired cardiac and renal function, enhanced EndMT, and lower A2AR expression. Spironolactone significantly up-regulated A2AR expression and inhibited EndMT in vivo and in vitro. Moreover, spironolactone improved cardiorenal remodeling and reduced dysfunction. These changes were exacerbated by administration of ZM241385. Together, these findings show that spironolactone up-regulated A2AR to reduce EndMT and ameliorate cardiorenal fibrosis.Significance: The anti-fibrotic effects of spironolactone may partly depend on the up-regulation of A2AR, and that A2AR might be a potential therapeutic target for the treatment of cardiorenal syndrome.