Figure 6

Schematic Diagram of CYP3A5′s Dual Role in the Regulation of Hypertension. Environmental factors (e.g., diet, chemical exposure, and stress) and homeostatic signaling mechanisms (i.e., Renin–Angiotensin–Aldosterone System (RAAS)) can alter renal and adrenal gland function to promote hypertension in humans. There is increasing evidence that renal CYP3A5 activity plays a dual role in modulating vitamin D- and glucocorticoid-hormone signaling cascades that drive HBP pathology. First, CYP3A5 activity can convert stress-related glucocorticoids (corticosterone and cortisol) to mineralocorticoids via 6β-hydroxylation, which enhances MR signaling and triggers sodium retention (via several transporter related mechanisms) and increased ROS production. This activity also silences glucocorticoid signaling (via ACTH and NFkB) and increases inflammation. Second, CYP3A5 can hijack endogenous vitamin D hormone signaling cascades by shunting 25-hydroxyvitamin D₃ metabolism from CYP27B1 (1α-hydroxylase) towards a 4β-hydroxylation pathway that limits 1,25-dihydroxyvitamin D₃ signaling via the VDR, reducing renin production that suppresses systemic RAAS activity. Thus, CYP3A5 appears to play a pathological endogenous role in many human polymorphs by regulating positive feedback loops that drives the accumulation of stress hormones and sodium in the renal proximal tubule cells. Sodium cationic-stabilization of G4-like elements in CYP3A5 intron 3 may exacerbate this hypertensive signaling arc in CYP3A5 *1/*3 and *3/*3 polymorphs, who may conditionally express the gene. This salt-sensitive positive feedback loop may mask any adaptive effects of the 6986A/G polymorphism (rs776746) by promoting stress- and dietary-sensitive expression of CYP3A5, complicating any GWAS studies focused on the *1/*3 or *3/*3 genotypes.