Adrenal Gq Signaling: Implications for Maintenance of Zonation and Steroidogenesis

Adrenal Cortex;Aldosterone;Mouse Model;hypertension;Gq signaling;Steroid;Physiology;Health Sciences;Molecular and Integrative Physiology

Taylor, MatthewShah, Yatrik M ;

University of Michigan

关键词: Adrenal Cortex;    Aldosterone;    Mouse Model;    hypertension;    Gq signaling;    Steroid;    Physiology;    Health Sciences;    Molecular and Integrative Physiology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/149906/motay_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

The human adrenal cortex can be divided into three zones that secrete distinct steroid hormones. The zona glomerulosa (ZG) produces aldosterone, a mineralocorticoid that is important for sodium/potassium homeostasis and blood pressure regulation. The zona fasciculata (ZF) produces cortisol, a glucocorticoid that participates in glucose homeostasis, and the zona reticularis serves as a secondary site for sex steroid production. The adrenal cortex undergoes cell renewal through centripetal displacement from the outer ZG to the inner adrenomedullary border where cells undergo apoptosis. Cells transition to the steroidogenic phenotype of each zone during the displacement process through gaining and losing zone-specific steroidogenic enzymes. There remain many unanswered questions regarding the cellular and molecular processes that regulate adrenocortical zonation. Understanding the mechanisms leading to cortical zonation and factors that cause dysregulation of steroid production could provide insight into adrenal physiology and disease.Primary aldosteronism (PA) is a common cause of hypertension that results from excess aldosterone production and inappropriate adrenal expression of aldosterone synthase (CYP11B2). Despite its high prevalence, there are few appropriate animal models for PA. Physiologic adrenal aldosterone production is regulated by the renin angiotensin-aldosterone system (RAAS) which is activated in states of low renal tubule sodium levels or intravascular volume, leading to increased renal sodium retention. Angiotensin II induces ZG aldosterone production via Gq-coupled receptors that trigger calcium signaling and transcription of CYP11B2. Recently, a series of DREADD (designer receptors exclusively activated by designer drugs) were developed to provide a chemogenetic method to modulate G-protein pathways. Included are transgenic receptors that stimulate Gq signaling only upon the binding of a synthetic ligand (clozapine N-oxide, CNO). This dissertation project tested the overall hypothesis that transgenic mice with targeted ZG/ZF GqDREADD expression would provide an inducible/reversible model for primary aldosteronism and a model to define the role of Gq signaling in functional adrenal zonation. In this study, we demonstrated that ASCre/+::hM3Dq mice respond to CNO treatment with an increase in aldosterone production and upregulation of Cyp11b2 expression in both the ZG and ZF. This increase in aldosterone caused renal negative feedback with suppression of renin in a manner similar to that seen in patients with PA. When mice were given CNO in conjunction to a high sodium diet, Cyp11b2 mRNA/protein and aldosterone were highly elevated, confirming that the induction of Cyp11b2 was autonomous and not RAAS dependent. Mice treated with CNO plus high sodium diet also developed hypertension in response to elevated aldosterone concentration. Analysis of adrenals from CNO treated mice demonstrated that ZF cells take-on some, but not all properties of ZG cells.The transcriptional, histological, hormonal and hypertensive phenotypes were all reversible upon CNO washout. In summary, this dissertation project resulted in the development of an inducible and reversible mouse model of adrenal-derived hyperaldosteronism and hypertension. The project also provides evidence that Gq signaling contributes to functional zonation and cellular ability to produce aldosterone. Future work will be needed to address the molecular mechanism by which Gq signaling activates Cyp11b2 expression and aldosterone production in ZF cells.This mouse model will also facilitate testing and discovery of therapeutic targets to block inappropriate aldosterone production and action in patients with PA.