Department of Urology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
PLoS One. 2013 Apr 23;8(4):e62399. doi: 10.1371/journal.pone.0062399. Print 2013.
To date, the available non-invasive remedies for primary aldosteronism are not satisfactory in clinical practice. The phosphoinositide 3-kinase (PI3Ks)/protein kinase B (PKB or AKT)/mammalian target of rapamycin (mTOR) signaling pathway is essential for tumorigenesis and metastasis in many types of human tumors, including renal cancer, adrenal carcinoma and pheochromocytoma. The possibility that this pathway is also necessary for the pathogenesis of primary aldosteronism has not yet been explored. To answer this question, we investigated the activity of the PI3K/AKT/mTOR signaling pathway in normal adrenal glands (NAGs), primary aldosteronism (PA) patients and NCI-H295R cells.
METHODOLOGY/PRINCIPAL FINDINGS: Between January 2005 and December 2011, we retrospectively reviewed the records of 45 patients with PA. We compared clinical characteristics (age, gender and biochemical data) and the expression of phospho-AKT (p-AKT), phospho-mTOR (p-mTOR), phospho-S6 (p-S6) and vascular endothelial growth factor (VEGF) by immunohistochemical staining and western blotting, analyzing 30 aldosterone-producing adenomas (APAs), 15 idiopathic hyperaldosteronism (IHA) tissues and 12 NAGs following nephrectomy for renal tumors (control group). Compared with the control group, most of the PA patients presented with polydipsia, polyuria, resistant hypertension, profound hypokalemia, hyperaldosteronemia and decreased plasma renin activity. Compared with normal zona glomerulosa, the levels of p-AKT, p-mTOR, p-S6 and VEGF were significantly upregulated in APA and IHA. No significant differences were found between APA and IHA in the expression of these proteins. Additionally, positive correlations existed between the plasma aldosterone levels and the expression of p-AKT and p-mTOR. In vitro studies showed that mTOR inhibitor rapamycin could inhibit cell proliferation in NCI-H295R cells in a dose- and time-dependent manner. Furthermore, this inhibitor also decreased aldosterone secretion.
Our data suggest that the PI3K/AKT/mTOR signaling pathway, which was overactivated in APA and IHA compared with normal zona glomerulosa, may mediate aldosterone hypersecretion and participate in the development of PA.
迄今为止，原发性醛固酮增多症的非侵入性治疗方法在临床上并不令人满意。磷酸肌醇 3-激酶（PI3Ks）/蛋白激酶 B（PKB 或 AKT）/哺乳动物雷帕霉素靶蛋白（mTOR）信号通路对于许多类型的人类肿瘤的肿瘤发生和转移是必不可少的，包括肾癌、肾上腺皮质癌和嗜铬细胞瘤。该途径对于原发性醛固酮增多症的发病机制是否也是必需的尚未得到探索。为了回答这个问题，我们研究了正常肾上腺（NAG）、原发性醛固酮增多症（PA）患者和 NCI-H295R 细胞中 PI3K/AKT/mTOR 信号通路的活性。
方法/主要发现：2005 年 1 月至 2011 年 12 月，我们回顾性分析了 45 例 PA 患者的病历。我们比较了临床特征（年龄、性别和生化数据）以及通过免疫组织化学染色和 Western 印迹分析磷酸化 AKT（p-AKT）、磷酸化 mTOR（p-mTOR）、磷酸化 S6（p-S6）和血管内皮生长因子（VEGF）的表达，分析了 30 例醛固酮瘤（APA）、15 例特发性醛固酮增多症（IHA）组织和 12 例因肾肿瘤行肾切除术的正常肾上腺（对照组）。与对照组相比，大多数 PA 患者表现为多饮、多尿、难治性高血压、严重低钾血症、高醛固酮血症和低血浆肾素活性。与正常球状带相比，APA 和 IHA 中 p-AKT、p-mTOR、p-S6 和 VEGF 的水平显著上调。APA 和 IHA 之间这些蛋白的表达无显著差异。此外，血浆醛固酮水平与 p-AKT 和 p-mTOR 的表达呈正相关。体外研究表明，mTOR 抑制剂雷帕霉素可剂量和时间依赖性地抑制 NCI-H295R 细胞的增殖。此外，该抑制剂还降低了醛固酮的分泌。
我们的数据表明，与正常球状带相比，APA 和 IHA 中过度激活的 PI3K/AKT/mTOR 信号通路可能介导醛固酮分泌过多，并参与 PA 的发生。
