Klotho/fgf23‐Independent and ERα Mediated Downregulation of NaPi‐IIa and NaPi‐IIc by Estrogen in the Mouse Kidney Proximal Tubule

Abstract

In these studies, we examined the effect of estrogen on renal inorganic phosphate (Pi) transport and the roles of its receptor isoforms (ERα and ERβ) and Klotho/FGF23 pathway in this effect in mice. Mice with null mutations (KO) of ERα or ERβ or Klotho and their wild‐type (WT) were placed in metabolic cages and injected daily with 17β‐estradiol or vehicle for 3 days. Food intake, urine volume and Pi excretion were measured daily. The results indicate that estrogen‐treated WT mice exhibited a significant increase in renal Pi wasting despite a reduction in food intake. Molecular studies showed a significant downregulation of NaPi‐IIa and NaPi‐IIc proteins with no change in their mRNA expression levels in the kidney. Estrogen‐induced reduction in food intake, phosphaturia and downregulation of NaPi‐IIa and NaPi‐IIc proteins were observed in ERβ KO but not in ERα KO mice. Further, Klotho KO mice exhibited a significant downregulation of NaPi‐IIa and hypophosphatemia in response to estrogen. In a cell line stably co‐expressing both ERα and ERβ, 24h of estrogen downregulated NaPi‐IIa protein, when cells are transiently transfected with a plasmid containing ORF‐3'UTR but not 5'UTR‐ORF of the mouse NaPi‐IIa transcript. In conclusion, estrogen causes phosphaturia in mice through the downregulation NaPi‐IIa and NaPi‐IIc protein abundance in the kidney. This effect is independent of Klotho/FGF23 pathway and is mediated through the activation of ERα. 3'UTR region of mouse NaPi‐IIa mRNA likely plays an important role in the inhibition of its translation by estrogen.