Characterization of pendrin in urinary extracellular vesicles in a rat model of aldosterone excess and in human primary aldosteronism.
Characterization of pendrin in urinary extracellular vesicles in a rat model of aldosterone excess and in human primary aldosteronism.
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DOI：
10.1038/s41440-021-00710-5
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Shibata S
中科院分区：
文献类型：
--
作者：
Ochiai-Homma F;Kuribayashi-Okuma E;Tsurutani Y;Ishizawa K;Fujii W;Odajima K;Kawagoe M;Tomomitsu Y;Murakawa M;Asakawa S;Hirohama D;Nagura M;Arai S;Yamazaki O;Tamura Y;Fujigaki Y;Nishikawa T;Shibata S
Pendrin是一种氯离子−/HCO3−交换器，选择性地存在于肾脏的间质细胞中。虽然实验研究已经证明，垂体素调节肾素-血管紧张素-醛固酮系统下游的血压，但它在人类高血压中的作用尚不清楚。在这里，我们分析了从30例原发性醛固酮增多症(PA)患者和一种醛固酮过多的大鼠模型中分离的尿液细胞外小泡(UEV)中膜蛋白的定量变化。Western印迹分析表明，在人和大鼠的uEV中，Pendrin以二聚体和单体的形式存在。在持续输注醛固酮的同时或不同时给予选择性盐皮质激素受体(MR)拮抗剂艾萨色酮的啮齿动物模型中，uEV中的垂垂蛋白水平以及上皮性Na+通道(ENaC)和钠氯共转运体(NCC)的水平与肾脏的丰度高度相关。在PA患者中，通过肾上腺切除或药物MR阻滞剂，uEV中的垂蛋白水平比基线降低了49%。相关分析显示，治疗后腹股沟蛋白减少的幅度与基线的醛固酮/肾素比值(ARR)显著相关。最后，对PA患者的横断面分析证实了uEVS中ARR和Pendrin水平之间的显著相关性。这些数据与显示旁腺素在醛固酮过剩中的作用的实验研究是一致的，并表明旁腺素在人类PA中的丰度通过治疗干预而减弱。我们的研究还表明，uEV中的垂蛋白分析以及其他蛋白质有助于了解高血压疾病的病理生理学。
Pendrin is a Cl−/HCO3− exchanger selectively present in the intercalated cells of the kidney. Although experimental studies have demonstrated that pendrin regulates blood pressure downstream of the renin-angiotensin-aldosterone system, its role in human hypertension remains unclear. Here, we analyzed the quantitative changes in pendrin in urinary extracellular vesicles (uEVs) isolated from a total of 30 patients with primary aldosteronism (PA) and from a rat model of aldosterone excess. Western blot analysis revealed that pendrin is present in dimeric and monomeric forms in uEVs in humans and rats. In a rodent model that received continuous infusion of aldosterone with or without concomitant administration of the selective mineralocorticoid receptor (MR) antagonist esaxerenone, pendrin levels in uEVs, as well as those of epithelial Na+ channel (ENaC) and Na-Cl-cotransporter (NCC), were highly correlated with renal abundance. In patients with PA, pendrin levels in uEVs were reduced by 49% from baseline by adrenalectomy or pharmacological MR blockade. Correlation analysis revealed that the magnitude of pendrin reduction after treatment significantly correlated with the baseline aldosterone-renin ratio (ARR). Finally, a cross-sectional analysis of patients with PA confirmed a significant correlation between the ARR and pendrin levels in uEVs. These data are consistent with experimental studies showing the role of pendrin in aldosterone excess and suggest that pendrin abundance is attenuated by therapeutic interventions in human PA. Our study also indicates that pendrin analysis in uEVs, along with other proteins, can be useful to understand the pathophysiology of hypertensive disorders.
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