Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Stomatological Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an 710004, China.
Life Sci. 2019 May 1;224:177-186. doi: 10.1016/j.lfs.2019.01.017. Epub 2019 Jan 15.
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.
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-β 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.
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.
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.
心脏肾综合征的发病机制复杂，尚未完全阐明；纤维化似乎是这些疾病病理生理学的主要驱动因素。螺内酯可通过抑制内皮-间充质转化（EndMT）来减少心脏或肾脏纤维化。螺内酯的保护作用可能依赖于激活腺苷受体，但腺苷 A2A 受体（A2AR）的作用尚不清楚。我们假设螺内酯可能通过调节 A2AR 来抑制 EndMT 并减少心脏肾重塑。
通过皮下注射异丙肾上腺素（Iso）建立肾脏损伤后继发心力衰竭的大鼠模型。评估心脏和肾脏功能、纤维化、EndMT 标志物、腺苷和 A2AR 表达。使用 TGF-β诱导原代人脐静脉内皮细胞（HUVECs）的 EndMT。将大鼠或细胞分为四组：单独用螺内酯或与 A2AR 拮抗剂 ZM241385 联合治疗或两者均不治疗，并与正常对照组进行比较。
异丙肾上腺素处理的大鼠表现出心脏和肾脏纤维化、心脏和肾脏功能受损、增强的 EndMT 和较低的 A2AR 表达。螺内酯在体内和体外均显著上调 A2AR 表达并抑制 EndMT。此外，螺内酯改善了心脏肾重塑并减少了功能障碍。这些变化在用 ZM241385 处理时加剧。综上所述，这些发现表明螺内酯通过上调 A2AR 减少 EndMT 并改善心脏肾纤维化。
螺内酯的抗纤维化作用可能部分依赖于 A2AR 的上调，A2AR 可能是治疗心脏肾综合征的潜在治疗靶点。
