Physiological and Pathological Roles in Human Adrenal of the Glomeruli-Defining Matrix Protein NPNT (Nephronectin)
Year: 2017
Type: article
Abstract: 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 NPNT ( nephronectin ) 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 CTNNB1 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 NPNT 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 NPNT 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.
Source: Hypertension
Institutions: Queen Mary University of London, University of Cambridge, University of Mississippi Medical Center, University of Mississippi, MRC Cancer Unit, Hutchison/MRC Research Centre, Wellcome/MRC Institute of Metabolic Science, G.V. (Sonny) Montgomery VA Medical Center, William Harvey Research Institute, Addenbrooke's Hospital, NIHR Cambridge Biomedical Research Centre
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,771
Awards: Interdisciplinary Training Programme for Clinicians in Translational Medicine and Therapeutics at the University of Cambridge: Support for the 2009 MPhil appointments., NIHR Senior Investigator Award, Do somatic mutations of an L-type Ca++ channel in aldosterone-producing adenomas of the adrenal indicate a novel mechanism and target for regulating aldosterone production?, G9000230881
OpenAlex ID: W2606349786