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

Marzia Scortegagna1, Annabel Berthon2, Nikolaos Settas2

  • 1Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.

JCI Insight
|December 8, 2017
PubMed

Insights

The ubiquitin ligase Siah1 plays a key role in adrenal gland development and primary aldosteronism (PA). Loss of Siah1 function increases aldosterone and impacts adrenal gland structure, offering new therapeutic targets for hypertension.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cardiovascular Disease Research

Background:

  • Primary and secondary hypertension are significant global risk factors for cardiovascular disease.
  • Primary aldosteronism (PA), characterized by elevated aldosterone secretion, is a major contributor to secondary hypertension.

Purpose of the Study:

  • To investigate the role of the ubiquitin ligase Siah1 in adrenal gland development and its involvement in primary aldosteronism (PA).

Main Methods:

  • Utilized Siah1a knockout (Siah1a-/-) mouse models to study adrenal gland morphology and function.
  • Analyzed gene expression related to catecholamine biosynthesis, cAMP signaling, retinoic acid signaling, and cholesterol biosynthesis.
  • Investigated the Siah1-PIAS1 interaction and its effect on LXR activity.
  • Sequenced SIAH1 in patients with PA to identify functional variants.

Main Results:

  • Siah1a-/- mice displayed altered adrenal gland morphology, including a diminished X-zone, enlarged medulla, and dysregulated glomerulosa zonation.
  • These mice exhibited increased aldosterone levels, elevated aldosterone target gene expression, and reduced plasma potassium.
  • Loss of Siah1 resulted in increased PIAS1 expression, which suppressed LXR, a key regulator of cholesterol.
  • PA patients with SIAH1 variants showed impaired ubiquitin ligase activity and elevated PIAS1.

Conclusions:

  • The Siah1-PIAS1 axis is crucial for adrenal gland organization and function.
  • Dysregulation of this axis contributes to hyperaldosteronism and hypertension.
  • SIAH1 and PIAS1 represent potential therapeutic targets for managing hyperaldosteronism.

Keywords:
Cell BiologyEndocrinologyGenetic diseasesMouse modelsUbiquitin-proteosome system

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