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JCI Insight. 2017 Dec 7;2(23). pii: 97128. doi: 10.1172/jci.insight.97128.

The E3 ubiquitin ligase Siah1 regulates adrenal gland organization and aldosterone secretion.

Author information

1
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
2
Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA.
3
Department of Comparative Medicine, Stanford University Medical Center, Stanford, California, USA.
4
Technion Integrated Cancer Center, Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.

Abstract

Primary and secondary hypertension are major risk factors for cardiovascular disease, the leading cause of death worldwide. Elevated secretion of aldosterone resulting from primary aldosteronism (PA) is a key driver of secondary hypertension. Here, we report an unexpected role for the ubiquitin ligase Siah1 in adrenal gland development and PA. Siah1a-/- mice exhibit altered adrenal gland morphology, as reflected by a diminished X-zone, enlarged medulla, and dysregulated zonation of the glomerulosa as well as increased aldosterone levels and aldosterone target gene expression and reduced plasma potassium levels. Genes involved in catecholamine biosynthesis and cAMP signaling are upregulated in the adrenal glands of Siah1a-/- mice, while genes related to retinoic acid signaling and cholesterol biosynthesis are downregulated. Loss of Siah1 leads to increased expression of the Siah1 substrate PIAS1, an E3 SUMO protein ligase implicated in the suppression of LXR, a key regulator of cholesterol levels in the adrenal gland. In addition, SIAH1 sequence variants were identified in patients with PA; such variants impaired SIAH1 ubiquitin ligase activity, resulting in elevated PIAS1 expression. These data identify a role for the Siah1-PIAS1 axis in adrenal gland organization and function and point to possible therapeutic targets for hyperaldosteronism.

KEYWORDS:

Cell Biology; Endocrinology; Genetic diseases; Mouse models; Ubiquitin-proteosome system

PMID:
29212953
PMCID:
PMC5752272
DOI:
10.1172/jci.insight.97128
[Indexed for MEDLINE]
Free PMC Article

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