Aldosterone and Ang II induce upregulation of fgf23 mRNA expression in animal cardiac myocytes, suggesting that the local intracardiac RAAS can induce FGF23 activation [63].

Conversely, FGF23 can induce AGT expression. Moreover, Ang II stimulates FGF23 production [12, 63, 71] and its expression with the coreceptor Klotho in the heart.

The additive effects of locally activated RAAS and FGF23 acting in concert reduce Klotho and, concurrent with elevated bone-derived circulating FGF23 levels, promotes cardiac fibrosis in CKD.

Ang II can upregulate bone expression of FGF23 [24] and increase circulating FGF23 levels.

Aldosterone stimulates bone expression of FGF23 by increased cytosolic Ca, mediated by serum/glucocorticoid regulated kinase 1 and store-operated Ca entry [24].

FGF23 inhibits 1-α-hydroxylase activity [75]. The resulting reduced 1,25(OH)₂D levels and tissue VDR expression favor renin upregulation with activation of the ACE/Ang II component of the RAAS [73, 74] and suppression of ACE2/Ang-(1–7) [65, 66].

Adipocyte-derived hormone leptin is a direct regulator of aldosterone secretion. Leptin directly stimulates FGF23 synthesis in bone cells in ob/ob mice. Leptin stimulates FGF23 expression in bone and suppresses renal 1,25 (OH)₂D₃ synthesis in leptin-deficient mice [82], suggesting that leptin may be an endocrine or paracrine regulator of FGF23 production in humans. Consequently, aldosterone and leptin act to concurrently upregulate bone FGF23 production and contribute to elevate circulating FGF23 levels.