Evaluation of an aldosterone synthase-targeting compound in HAC-15 cells: insights into targeted therapy for primary aldosteronism

Aldosterone is a mineralocorticoid hormone synthesised from cholesterol in the zona glomerulosa cells of the adrenal cortex, with aldosterone synthase (encoded by CYP11B2 gene) catalysing the final step. Its synthesis is primarily controlled by the renin-angiotensin-aldosterone system (RAAS). It maintains blood pressure by increasing renal sodium absorption in response to low blood pressure. However, excess aldosterone production, hyperaldosteronism, leads to increased sodium reabsorption in kidneys, leading to water retention, and ultimately increasing blood volume and pressure. Therapeutic approaches vary from mineralocorticoid receptor antagonists (MRAs) to adrenalectomy. The aim of this study was to evaluate the effects of two new aldosterone synthase inhibitors on aldosterone production in a model of human adrenocortical cells (HAC-15). Cells were cultured and exposed to a standard starvation and stimulation protocol. Effects of the drug were assessed using MTT test to evaluate toxicity and cell viability; protein extraction and purification; BCA to measure total protein levels; ELISA to quantify aldosterone and cortisol levels. Results of the experiments demonstrated that neither compound showed cytotoxic effects on the cells, suggesting their safety within the tested concentrations. Furthermore, aldosterone production was significantly reduced in response to treatment, while cortisol production remained unaffected, confirming the selectivity of the compounds for CYP11B2. These findings showed the potential for new aldosterone synthase inhibitors, highlighting their efficacy and selectivity in reducing aldosterone synthesis without impairing cortisol levels. While further validation is required, the ongoing research contributes to the development of more targeted and safer therapeutic approaches at modulating RAAS in hypertensive patients.