Acute and chronic adaptation of renal phosphate transporters to dietary phosphate intake in mice demonstrates importance of NaPi‐IIa and upregulation despite high FGF23 levels

Renal inorganic phosphate (Pi) reabsorption is mediated by the sodium‐dependent phosphate transporters, NaPi‐IIa, NaPi‐IIc, and Pit2 in the brush border membrane of proximal tubule (BBM). Dietary Pi intake regulates these transporters, partly via hormones such as PTH and FGF23. We investigated the time course of adaption in WT mice and the relative contribution of NaPi‐IIa in the adaptive response in NaPiIIa KO mice. Mice received 5 days a high Pi (HPD) or low Pi (LPD) diet. On day 5, some mice were switched for 4 hrs to LPD or HPD. Serum Pi was similar under chronic diets in WT and KO, but KO mice reduced their serum Pi when acutely switched to LPD. Urinary Pi excretion was similar in WT and KO mice under HPD, but under LPD KO mice exhibited a constant urinary Pi loss compensated by a higher intestinal Pi absorption. During the acute HPD‐to‐LPD switch, KO mice exhibited a delayed decrease in urinary Pi excretion. In WT mice PTH and NaPi‐IIa plasma membrane expression were acutely regulated by Pi diet, whereas c‐term FGF23 levels were still high after 8 hrs HPD‐to‐LPD switch. In BBM vesicles, Pi transport activity and plasma membrane NaPi‐IIa but not NaPi‐IIc or Pit2 abundance acutely adapted to diets in WT mice. In KO, BBM vesicles transport activity was lower under all conditions and did not adapt. Thus, only NaPi‐IIa mediates the fast adaptation to Pi intake and is upregulated during the adaptation to low Pi diet despite high FGF23 levels.