The E3 ubiquitin ligase Siah1 regulates adrenal gland organization and aldosterone secretion
Marzia Scortegagna, … , Constantine A. Stratakis, Ze’ev A. Ronai
Marzia Scortegagna, … , Constantine A. Stratakis, Ze’ev A. Ronai
Published December 7, 2017
Citation Information: JCI Insight. 2017;2(23):e97128. https://doi.org/10.1172/jci.insight.97128.
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Research Article Cell biology Endocrinology Article has an altmetric score of 52

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

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.

Authors

Marzia Scortegagna, Annabel Berthon, Nikolaos Settas, Andreas Giannakou, Guillermina Garcia, Jian-Liang Li, Brian James, Robert C. Liddington, José G. Vilches-Moure, Constantine A. Stratakis, Ze’ev A. Ronai

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Figure 1

Altered morphology of the adrenal glands with diminished X-zone in Siah1a–/– mice.

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Altered morphology of the adrenal glands with diminished X-zone in Siah1...
(A–C) H&E staining of 21-day-old WT adrenal glands and Siah1a–/– (Siah1a KO) mice at low (A) and high (B) magnification and quantitation of the X- zone (C). Five mice were analyzed for X-zone quantitation. *P < 0.05, compared with WT. Glands from Siah1a KO mice show aberrant morphology, with a smaller X-zone. The white and yellow lines indicate the medulla (M) and X-zone, respectively. Scale bar: 100 μm. (D) Adrenal gland weights relative to body weights of 21-day-old Siah1a–/– mice and WT littermates (n = 6). (E) Representative immunofluorescence for the X-zone marker, 20-αHSD, in 21-day-old-WT and Siah1a–/– adrenals. Although 20-αHSD expression is found in both WT and KO adrenals, its expression is significantly reduced in Siah1a–/– mice. (F) qPCR analysis of 20αHSD, and PIK3C2γ expression in the adrenal glands of 21-day-old Siah1a–/– and WT mice (n = 4). **P < 0.005, ***P < 0.0005, compared with WT. Data are shown as mean ± SEM. Statistical analysis was performed using t test.