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

JCI Insight. 2017 Dec 7;2(23):e97128. doi: 10.1172/jci.insight.97128.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Glands / metabolism*
  • Adrenal Glands / pathology
  • Adrenal Medulla / pathology
  • Adult
  • Aldosterone / metabolism*
  • Animals
  • Cholesterol / biosynthesis
  • Female
  • Gene Expression Regulation / physiology
  • Humans
  • Hyperaldosteronism / genetics
  • Hyperaldosteronism / metabolism
  • Kidney / metabolism
  • Male
  • Mice, Knockout
  • Middle Aged
  • Mutation
  • Nuclear Proteins / genetics
  • Potassium / blood
  • Protein Inhibitors of Activated STAT / biosynthesis
  • Protein Inhibitors of Activated STAT / genetics
  • Protein Inhibitors of Activated STAT / metabolism
  • Proteins / genetics
  • Proteins / physiology*
  • Signal Transduction / genetics
  • Small Ubiquitin-Related Modifier Proteins / metabolism
  • Tretinoin / physiology
  • Ubiquitin-Protein Ligases / genetics
  • Zona Glomerulosa / metabolism
  • Zona Glomerulosa / pathology


  • Nuclear Proteins
  • PIAS1 protein, human
  • Pias1 protein, mouse
  • Protein Inhibitors of Activated STAT
  • Proteins
  • Small Ubiquitin-Related Modifier Proteins
  • Aldosterone
  • Tretinoin
  • Cholesterol
  • Siah1a protein, mouse
  • Ubiquitin-Protein Ligases
  • seven in absentia proteins
  • Potassium