title: Visinin-like 1 is upregulated in aldosterone-producing adenomas with KCNJ5 mutations and protects from calcium-induced apoptosis.
abstract: Visinin-like 1 (VSNL1) is upregulated in aldosterone-producing adenomas (APAs) compared with normal adrenals. We demonstrate that VSNL1 overexpression in adrenocortical carcinoma cells (NCI H295R) upregulates basal and angiotensin II-stimulated CYP11B2 gene expression 3.2- and 1.5-fold, respectively. Conversely, silencing VSNL1 by RNA interference decreases angiotensin II-stimulated CYP11B2 expression and aldosterone secretion by 41.0% and 34.5%, respectively. Mutations in the potassium channel KCNJ5 have been identified in APAs that result in sodium influx and membrane depolarization and are postulated to result in calcium influx in adrenal glomerulosa cells. VSNL1 and CYP11B2 are 8.1- and 6.0-fold more highly expressed, respectively, in APAs harboring KCNJ5 mutations compared with those without, and the upregulation of VSNL1 in these APAs accounts for the overexpression of VSNL1 in the total APA sample set compared with normal adrenals. Silencing VSNL1 in H295R cells renders them sensitive to ionomycin-induced apoptosis, indicating that VSNL1 protects these cells against calcium-induced cell death. Concomitant expression of mutated KCNJ5 (G151R) and silencing VSNL1 results in apoptosis of H295R cells, an effect that is blocked by nifedipine and is absent using a control small-interfering RNA or when wild-type KCNJ5 is expressed and VSNL1 is silenced. These data demonstrate that VSNL1 plays a dual function in vitro in the regulation of CYP11B2 gene expression and in the inhibition of calcium-induced apoptosis. In addition, VSNL1 may play a role in the pathophysiology of APAs harboring mutations in the potassium channel KCNJ5 via its antiapoptotic function in response to calcium cytotoxicity and its effect on aldosterone production.
authors.affiliation: Division of Internal Medicine and Hypertension, University of Torino, Torino, Italy. tracyann.williams@unito.it
authors.forename: Tracy Ann
authors.initials: TA
authors.lastname: Williams
authors.forename: Silvia
authors.initials: S
authors.lastname: Monticone
authors.forename: Valentina
authors.initials: V
authors.lastname: Crudo
authors.forename: Richard
authors.initials: R
authors.lastname: Warth
authors.forename: Franco
authors.initials: F
authors.lastname: Veglio
authors.forename: Paolo
authors.initials: P
authors.lastname: Mulatero
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018268:Adrenocortical Carcinoma / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000450:Aldosterone / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019405:Cytochrome P-450 CYP11B2 / Q000378:metabolism; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics*; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D009154:Mutation / Q000235:genetics*; D051596:Neurocalcin / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C484274:KCNJ5 protein, human; D051596:Neurocalcin; D034741:RNA, Small Interfering; C496688:VSNL1 protein, human; D000450:Aldosterone; D015759:Ionomycin; D019405:Cytochrome P-450 CYP11B2; D009543:Nifedipine; D002118:Calcium