Teo Ada Ee Der, Garg Sumedha, Johnson Timothy Isaac, Zhao Wanfeng, Zhou Junhua, Gomez-Sanchez Celso Enrique, Gurnell Mark, Brown Morris Jonathan
From the Clinical Pharmacology Unit, Centre for Clinical Investigation, Addenbrooke's Hospital (A.E.D.T., S.G., J.Z., M.J.B.), Tissue Bank, Department of Histopathology, Addenbrooke's Hospital (W.Z.), NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital (M.G.), MRC Cancer Unit, Hutchison/MRC Research Centre (T.I.J.), and Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science (M.G.), University of Cambridge, United Kingdom; Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine & Dentistry, Queen Mary University of London, United Kingdom (J.Z., M.J.B.); Division of Endocrinology, Department of Medicine, The University of Mississippi Medical Centre, Jackson (C.E.G.-S.); and Research and Medicine Services, G.V. (Sonny) Montgomery VA Medical Centre, Jackson, MS (C.E.G.-S.).
Hypertension. 2017 Jun;69(6):1207-1216. doi: 10.1161/HYPERTENSIONAHA.117.09156. Epub 2017 Apr 17.
Primary aldosteronism is a common cause of hypertension, which becomes refractory if undiagnosed, but potentially curable when caused by an aldosterone-producing adenoma (APA). The discovery of somatic mutations and differences in clinical presentations led to recognition of small but common zona glomerulosa (ZG)-like adenomas, distinct from classical large zona fasciculata-like adenomas. The inverse correlation between APA size and aldosterone synthase expression prompted us to undertake a systematic study of genotype-phenotype relationships. After a microarray comparing tumor subtypes, in which () was the most highly (>12-fold) upregulated gene in ZG-like APAs, we aimed to determine its role in physiological and pathological aldosterone production. NPNT was identified by immunohistochemistry as a secreted matrix protein expressed exclusively around aldosterone-producing glomeruli in normal adrenal ZG and in aldosterone-dense ZG-like APAs; the highest expression was in ZG-like APAs with gain-of-function mutations, whose removal cured hypertension in our patients. NPNT was absent from normal zona fasciculata, zona fasciculata-like APAs, and ZG adjacent to an APA. NPNT production was regulated by canonical Wnt pathway, and overexpression or silencing increased or reduced aldosterone, respectively. NPNT was proadhesive in primary adrenal and APA cells but antiadhesive and antiapoptotic in immortalized adrenocortical cells. The discovery of in the adrenal helped recognition of a common subtype of APAs and a pathway by which Wnt regulates aldosterone production. We propose that this arises through NPNT's binding to cell-surface integrins, stimulating cell-cell contact within glomeruli, which define ZG. Therefore, NPNT or its cognate integrin could present a novel therapeutic target.
原发性醛固酮增多症是高血压的常见病因，若未被诊断，病情会变得难以控制，但由醛固酮分泌性腺瘤（APA）引起的原发性醛固酮增多症则有潜在治愈可能。体细胞突变的发现以及临床表现的差异促使人们认识到存在一些小而常见的、类似球状带（ZG）的腺瘤，它们与典型的大的、类似束状带的腺瘤不同。APA大小与醛固酮合酶表达之间的负相关关系促使我们对基因型-表型关系进行系统研究。在对肿瘤亚型进行微阵列比较后，其中（）是类似ZG的APA中上调程度最高（>12倍）的基因，我们旨在确定其在生理性和病理性醛固酮生成中的作用。通过免疫组织化学鉴定NPNT为一种分泌性基质蛋白，仅在正常肾上腺ZG以及醛固酮密集的类似ZG的APA中产生醛固酮的肾小球周围表达；在具有功能获得性突变的类似ZG的APA中表达最高，去除这些突变可治愈我们患者的高血压。正常束状带、类似束状带的APA以及与APA相邻的ZG中均不存在NPNT。NPNT的产生受经典Wnt信号通路调控，其过表达或沉默分别增加或减少醛固酮分泌。NPNT在原代肾上腺细胞和APA细胞中具有促黏附作用，但在永生化肾上腺皮质细胞中具有抗黏附和抗凋亡作用。在肾上腺中发现NPNT有助于识别APA的一种常见亚型以及Wnt调节醛固酮生成的途径。我们认为这是通过NPNT与细胞表面整合素结合，刺激肾小球内的细胞-细胞接触而产生的，肾小球定义了ZG。因此，NPNT或其相关整合素可能是一个新的治疗靶点。
