Figure 2. FGF-23 and Vitamin D exhibit counter-regulator effects.

A) Bone-Kidney Endocrine Axis. FGF-23 produced in bone regulates FGFR/α-Klotho complexes in the kidney to inhibit phosphate reabsorption and lower circulating 1,25(OH)₂D through suppression of Cyp27b1 synthetic and activation of Cyp24a1 degradative pathways. FGF-23 also suppresses ACE2 and increases distal tubule sodium reabsorption, leading to increased blood pressure. FGF-23 also regulates the expression of α-Klotho, which is released into the circulation by ectodomain shedding and acts as a hormone with FGF-23 independent effects. 1,25(OH)₂D stimulates systemic release of FGF-23 from bone that in turn suppresses 1,25(OH)₂D release from the kidney to create a negative feedback loop. A positive feedback cardiovascular loop is theoretically created by Ang II and SNS stimulation of FGF-23 expression by bone and effects of circulating FGF-23 to decrease ACE2 and increase renal sodium reabsorption. B) FGF-23 and α-Klotho are also expressed in activated macrophages, which creates a pro-inflammatory paracrine FGF-23 signaling pathway. FGF-23 expression in macrophages and stimulation of TNF-α may offset the anti-inflammatory effects of vitamin D on the innate immune response. In macrophages, 1,25(OH)₂D may suppress FGF-23 expression. C) A model of FGF-23 cardiotoxicity derived from FGF-23 effects on the kidney and/or the ectopic expression of FGF-23/α-Klotho in infiltrating macrophages. Stimulation of FGF-23 release into the circulation by RAS, SNS, or oxidative stress or local production of FGF-23 in macrophages could attenuate the beneficial effects of Vitamin D on the cardiovascular and innate immune responses.