Inorganic phosphate (Pi) is an essential mineral, and its plasma levels are tightly regulated. In mammals, kidneys are critical for maintaining Pi-homeostasis through mechanisms that ultimately regulate the expression of the Na+/Pi cotransporters NaPi-IIa and NaPi-IIc in proximal tubules. Inositol pyrophosphate 5-IP7, generated by inositol hexakisphosphate kinases (IP6Ks), is a main regulator of Pi-metabolism in yeast and plants. IP6Ks are conserved in mammals but their role in Pi-metabolism in vivo remains unexplored.

We used in vitro (opossum kidney cells) and in vivo (renal tubular-specific Ip6k1/2-/-mice) models to analyze the role of IP6K1/2 in Pi-homeostasis in mammals.

In both systems, Ip6k1 and Ip6k2 are responsible for synthesis of 5-IP7. Depletion of Ip6k1/2 in vitro reduces Pi-transport and mRNA expression of Na+/Pi cotransporters, and it blunts Pi-transport adaptation to changes in ambient Pi. Renal ablation of both kinases in mice also downregulates the expression of NaPi-IIa and NaPi-IIc and lowers the uptake of Pi into proximal renal brush border membranes. In addition, the absence of Ip6k1 and Ip6k2 reduces the plasma concentration of fibroblast growth factor 23 and increases bone resorption, despite of which homozygous males develop hypophosphatemia. Ip6k1/2-/- mice also show increased diuresis, albuminuria, and hypercalciuria, though the morphology of glomeruli and proximal BBM seems unaffected.

Depletion of renal Ip6k1/2 in mice alters Pi-homeostasis, but also dysregulates other kidney functions.