The E3 ubiquitin ligase Siah1 regulates adrenal gland organization and hyperaldosteronism

Primary and secondary hypertension are major risk factors for cardiovascular disease. Elevated secretion of aldosterone resulting from primary aldosteronism (PA) is a key driver of secondary hypertension. Here, we identify an unexpected role for the ubiquitin ligase Siah1 in adrenal gland development and PA. Siah1a-/- mice exhibit altered adrenal gland morphology, as reflected by dysregulated zonation of the glomerulosa, 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 PIAS1, an E3 SUMO-protein ligase implicated in the suppression of LXR. Notably, SIAH1 sequence variants which impaired SIAH1 ubiquitin ligase activity, resulting in elevated PIAS1 expression, were identified in patients with PA. The involvement of Siah1–PIAS1 in adrenal gland organization and function points to a possible new therapeutic target for hyperaldosteronism. Overall design: 1 adrenal gland from WT male mouse, 1 adrenal gland from WT female mouse, 1 adrenal gland from siah1a KO male mouse, 1 adrenal gland fromsiah1a KO female mouse, 1 adrenal gland from WT male mouse injected IP with 100ug/kg of ACTH for 1 hour, 1 adrenal gland from WT female mouse injected IP with 100ug/kg of ACTH for 1 hour, 1 adrenal gland from siah1a KO male mouse injected IP with 100ug/kg of ACTH for 1 hour, 1 adrenal gland fromsiah1a KO female mouse injected IP with 100ug/kg of ACTH for 1 hour.