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Researchers identify new mechanism behind primary aldosteronism
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Researchers have identified what they called an “unexpected role” for a protein involved in adrenal gland development and primary aldosteronism, potentially opening a new pathway for therapeutic agents to treat the condition, according to an announcement from Sanford-Burnham Prebys Medical Discovery Institute.
The findings, published in JCI Insight, identified a role for the Siah1-PIAS1 axis in adrenal gland organization. Loss of Siah1a results in hyperaldosteronism, a disorder strongly associated with hypertension in humans. The research was done in collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Human Development, part of the National Institutes of Health.
"Our research, based on a genetic model, identifies an unexpected layer in the regulation of adrenal gland development and in hyperaldosteronism," Ze'ev Ronai, PhD, chief scientific advisor of SBP, said in a press release. "The findings are important because they identify a previously unknown regulatory axis that controls aldosterone levels, thus offering new avenues for drug discovery of secondary hypertension.”
"We initially found that the structure of the adrenal glands in mice lacking the Siah1 ubiquitin ligase gene was markedly different, and they had increased levels of aldosterone," Marzia Scortegagna, PhD, staff scientist in Ronai's laboratory, said in the release. "Upon further examination, we noted elevated levels of PIAS1, a Siah1-controlled protein, which is a key regulator of cholesterol biosynthesis, the precursor for aldosterone synthesis."
Ronai said that Siah1 is a ubiquitin ligase that plays an important role in many cellular pathways implicated in neurodegeneration and cancer, adding that the team’s result is the first to identify the role of this gene in hyperaldosteronism through its control of cholesterol biosynthesis involving PIAS1.
In their findings, the researchers noted that observations in the genetic mouse model were validated by the finding that SIAH1 and PIAS1 expression are dysregulated in the adrenal glands of patients with primary aldosteronism. Collectively, they noted, these data uncover a role for the Siah1-PIAS1 regulatory axis in aldosterone secretion.
“In particular, our finding that changes in retinoic-acid signaling and cholesterol biosynthesis contribute to adrenal gland dysfunction and hyperaldosteronism raises the possibility that drugs selectively targeting these pathways might offer a new therapeutic modality for [primary aldosteronism], a disease that currently lacks effective therapy beyond mineralocorticoid receptor blockade,” the researchers wrote.
Disclosures: The authors report no relevant financial disclosures.
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