The adrenal cortex is responsible for adrenal steroid production and is anatomically divided into three distinct zones producing different categories of steroid hormones (Merklin, 1962, Payne and Hales, 2004, Rainey et al., 2004). Zona glomerulosa is commissioned to produce mineralocorticoids (aldosterone), zona fasciculata glucocorticoids (cortisol), while zona reticularis produces androgens (Merklin, 1962, Payne and Hales, 2004, Rainey et al., 2004). Adrenocortical steroid hormones are essential in the processes of body homeostasis. Cholesterol is the precursor of all of them taken up into the adrenal gland from the blood, where it circulates bound to plasma proteins (Chang et al., 2006, Payne and Hales, 2004). Following cellular uptake, cytoplasmic cholesterol is transferred from the outer to the inner membrane of the mitochondria, by the steroidogenic acute regulatory protein (StAR) (Stocco, 2000). There, cholesterol undergoes several hydroxylations, oxidations, and other modifications by cytochrome P450 (CYP) enzymes, which convert it to pregnenolone, then progesterone, and ultimately to the end steroid hormone product, depending on the anatomical zone of the adrenal cortex (Gomez-Sanchez et al., 2014, Midzak and Papadopoulos, 2016). In zona glomerulosa cells, progesterone is converted to 11-deoxycorticosterone and transferred back to the mitochondria, where it becomes aldosterone via the action of aldosterone synthase (CYP11B2) (Arlt and Stewart, 2005, Bollag, 2014). Importantly, due to their high lipophilicity, no adrenal steroid hormone (including aldosterone) is stored in vesicles but rather gets synthesized and secreted instantly upon cell stimulation with specific stimuli (Holst, Soldin, Guo, & Soldin, 2004). Although other biologically active mineralocorticoids are synthesized by zona glomerulosa cells, aldosterone is the most potent one and a key component of the renin-angiotensin-aldosterone system (RAAS) or axis, responsible for blood sodium and potassium homeostasis, which, in turn, regulates blood volume and arterial pressure (Lymperopoulos and Aukszi, 2017, Lymperopoulos et al., 2019). The primary stimuli for aldosterone production are the octapeptide hormone angiotensin II (AngII) and hyperkalemia (high K+ levels in the blood). Notably, the contribution of adrenocorticotropic hormone (ACTH) is minimal, as it mainly induces cortisol synthesis in zona fasciculata (Spät & Hunyady, 2004).

A drop in renal perfusion pressure stimulates renin synthesis by the juxtaglomerular apparatus (JGA) cells. Renin, followed by angiotensin converting enzyme (ACE), ultimately form AngII (Nishiyama & Kim-Mitsuyama, 2010). AngII, being a peptide, cannot cross cell membranes and thus, uses two distinct G protein-coupled receptor (GPCR) types, AngII type 1 receptor (AT1R) and AT2R, to exert its effects in cells (de Gasparo, Catt, Inagami, Wright, & Unger, 2000). AT1R couples primarily to members of the Gq/11 family of guanine nucleotide-binding proteins (G proteins) (de Gasparo et al., 2000), whereas the AT2R, curiously, seems to activate none of the major G protein-dependent downstream signaling pathways (Zhang et al., 2017). It is mainly known to promote nitric oxide production and to counteract inflammation while its main function in most mammalian tissues appears to be opposing the cellular effects of its AT1R counterpart (Patel, Fatima, Ali, & Hussain, 2020). AT1R is known to also couple to Gi/o and Gs proteins, as well as to interact with numerous signal transducers and adapter proteins, the most important of which are the two βarrestins (βarrestin1 or Arrestin-2 and βarrestin2 or Arrestin-3) (Capote et al., 2015, Desimine et al., 2018, Siryk-Bathgate et al., 2013, Tóth et al., 2018, Turu et al., 2019). Unlike the AT2R, the AT1R has been extensively studied and is well documented to be involved in various pathophysiological processes, especially of the cardiovascular system, such as hypertension, cardiac hypertrophy and fibrosis, adverse remodeling, etc. (Imaizumi et al., 2013, Markan et al., 2019, Miura et al., 2006, Miura et al., 2011, Van Liefde and Vauquelin, 2009). This is why it represents one of the best known pharmacological targets for cardiovascular disorders, being targeted directly by angiotensin receptor blocker (ARB) drugs (“sartans”) and indirectly by ACE inhibitors and renin inhibitors (Imaizumi et al., 2013, Markan et al., 2019, Miura et al., 2006, Miura et al., 2011, Van Liefde and Vauquelin, 2009).