Fig. 1

Homeostatic functions of FGF23. Serum levels of phosphate are maintained within a tight range ([X′-X]) through constantly comparing the status quo (X) of circulating phosphate abundance with a predefined set-point (X′). If phosphate levels rise above the upper boundary of this range, FGF23 is induced, although the precise mechanism underlying phosphate-driven FGF23 secretion remains elusive. FGF23 restores phosphate homeostasis through its effects on the kidneys: In the proximal tubule, FGF23 reduces phosphate reabsorption by downregulating Natrium/Phosphate Cotransporters (NaP_is), inhibition of 25-OH-Vitamin D activation through downregulating CYP27A1 as well as enhanced catabolism of 25-OH-Vitamin-D via upregulation of CYP24A1. The latter two changes also decrease intestinal phosphate uptake. Moreover, FGF23 enhances sodium and chloride reabsorption in the distal tubule by fostering Na⁺/Cl⁻ Cotransporter (NCC) activity, which yields an expansion of extracellular volume (ECV). This, in turn, increases systemic as well as glomerular blood pressure (P_G), thereby enhancing net glomerular filtration pressure (NFP) and thus, phosphate filtration. The two opposing forces of P_G restricting NFP are the hydrostatic pressure within the capsular of Bowman (P_Bow) and glomerular capillary oncotic pressure (π_c), i.e., [NFP = P_G-(P_Bow + π_c)]. Collectively, these adaptations contribute to the phosphate-lowering effects of FGF23