The membrane cytoskeletal crosslinker ezrin is essential for the regulation of phosphate and calcium homeostasis

Abstract

Ezrin is a cross‐linker between the plasma membrane proteins and actin cytoskeleton. In the kidney, ezrin is mainly localized at brush border membrane of proximal tubules with a scaffolding protein, Na+/H+ exchanger regulatory factor (NHERF) 1. NHERF1 interacts with Na+/phosphate (Pi) cotransporter Npt2a. We focused on the physiological role of ezrin in the renal Pi reabsorption by using ezrin knockdown mice (Vil2kd/kd). The Vil2kd/kd mice exhibited hypophosphatemia, hypocalcemia, and osteomalacia. The reduced plasma concentration of Pi was attributed to the defective urinary Pi reabsorption. Immunofluorescence staining and immunoblotting revealed that the Npt2a and NHERF1 expressions at apical membrane of proximal tubules were markedly reduced in the kidney of Vil2kd/kd mice. On the other hand, urinary loss of Ca2+ was not observed in Vil2kd/kd mice. Plasma concentration of 1,25‐dihydroxyvitamin D was elevated following reduced plasma Pi level. Furthermore, bone mineral density in tibiae was significantly lowered in the adult and young Vil2kd/kd mice. These results suggest that ezrin is required for the regulation of systemic Pi homeostasis in vivo.