| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Edwards, Michael A. Kuick, Rork Sanjanwala, Aalok R. Hovelson, Daniel H. Nanba, Kazutaka Nishimoto, Koshiro Cani, Andi K. Tomlins, Scott A. Giordano, Thomas J. Liu, Chia-jen Gomez-sanchez, Celso E. Rainey, William E. |
| Description |
Author Affiliation: Nishimoto K ( Departments of Molecular and Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, MI 48109); Tomlins SA ( Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109); Kuick R ( Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109); Cani AK ( Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109); Giordano TJ ( Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109); Hovelson DH ( Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109); Liu CJ ( Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109); Sanjanwala AR ( Departments of Molecular and Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, MI 48109); Edwards MA ( Department of Surgery, Temple University School of Medicine, Philadelphia, PA 19140); Gomez-Sanchez CE ( Division of Endocrinology, G. V. (Sonny) Montgomery Veterans Affairs Medical Center and University of Mississippi Medical Center, Jackson, MS 39110.); Nanba K ( Departments of Molecular and Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, MI 48109); Rainey WE ( Departments of Molecular and Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, MI 48109); |
| Abstract |
Primary aldosteronism (PA) represents the most common cause of secondary hypertension, but little is known regarding its adrenal cellular origins. Recently, aldosterone-producing cell clusters (APCCs) with high expression of aldosterone synthase (CYP11B2) were found in both normal and PA adrenal tissue. PA-causing aldosterone-producing adenomas (APAs) harbor mutations in genes encoding ion channels/pumps that alter intracellular calcium homeostasis and cause renin-independent aldosterone production through increased CYP11B2 expression. Herein, we hypothesized that APCCs have APA-related aldosterone-stimulating somatic gene mutations. APCCs were studied in 42 normal adrenals from kidney donors. To clarify APCC molecular characteristics, we used microarrays to compare the APCC transcriptome with conventional adrenocortical zones [zona glomerulosa (ZG), zona fasciculata, and zona reticularis]. The APCC transcriptome was most similar to ZG but with an enhanced capacity to produce aldosterone. To determine if APCCs harbored APA-related mutations, we performed targeted next generation sequencing of DNA from 23 APCCs and adjacent normal adrenal tissue isolated from both formalin-fixed, paraffin-embedded, and frozen tissues. Known aldosterone driver mutations were identified in 8 of 23 (35%) APCCs, including mutations in calcium channel, voltage-dependent, L-type, 1D-subunit (CACNA1D; 6 of 23 APCCs) and ATPase, Na(+)/(K+) transporting, 1-polypeptide (ATP1A1; 2 of 23 APCCs), which were not observed in the adjacent normal adrenal tissue. Overall, we show three major findings: (i) APCCs are common in normal adrenals, (ii) APCCs harbor somatic mutations known to cause excess aldosterone production, and (iii) the mutation spectrum of aldosterone-driving mutations is different in APCCs from that seen in APA. These results provide molecular support for APCC as a precursor of PA. |
| ISSN |
00278424 |
| e-ISSN |
10916490 |
| Journal |
Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number |
33 |
| Volume Number |
112 |
| Language |
English |
| Publisher |
National Academy of Sciences |
| Publisher Date |
2015-08-01 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Adrenal Glands Metabolism Aldosterone Biosynthesis Mutation Adrenal Cortex Cytochrome P-450 CYP11B2 DNA Chemistry Gene Expression Regulation High-Throughput Nucleotide Sequencing Homeostasis Hyperaldosteronism Etiology Oligonucleotide Array Sequence Analysis Principal Component Analysis Sequence Analysis, DNA Sequence Analysis, RNA Transcriptome Zona Glomerulosa Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Multidisciplinary |
