title: Klotho/fibroblast growth factor 23- and PTH-independent estrogen receptor-α-mediated direct downregulation of NaPi-IIa by estrogen in the mouse kidney.
abstract: Estrogen treatment causes renal phosphate (Pi) wasting and hypophosphatemia in rats and humans; however, the signaling mechanisms mediating this effect are still poorly understood. To determine the specific roles of estrogen receptor isoforms (ERα and ERβ) and the Klotho pathway in mediating these effects, we studied the effects of estrogen on renal Pi handling in female mice with null mutations of ERα or ERβ or Klotho and their wild type (WT) using balance studies in metabolic cages. Estrogen treatment of WT and ERβ knockout (KO) mice caused a significant reduction in food intake along with increased renal phosphate wasting. The latter resulted from a significant downregulation of NaPi-IIa and NaPi-IIc protein abundance. The mRNA expression levels of both transporters were unchanged in estrogen-treated mice. These effects on both food intake and renal Pi handling were absent in ERα KO mice. Estrogen treatment of Klotho KO mice or parathyroid hormone (PTH)-depleted thyroparathyroidectomized mice exhibited a significant downregulation of NaPi-IIa with no change in the abundance of NaPi-IIc. Estrogen treatment of a cell line (U20S) stably coexpressing both ERα and ERβ caused a significant downregulation of NaPi-IIa protein when transiently transfected with a plasmid containing full-length or open-reading frame (ORF) 3'-untranslated region (UTR) but not 5'-UTR ORF of mouse NaPi-IIa transcript. In conclusion, estrogen causes phosphaturia and hypophosphatemia in mice. These effects result from downregulation of NaPi-IIa and NaPi-IIc proteins in the proximal tubule through the activation of ERα. The downregulation of NaPi-IIa by estrogen involves 3'-UTR of its mRNA and is independent of Klotho/fibroblast growth factor 23 and PTH signaling pathways.
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, University of Cincinnati, Cincinnati, Ohio;
authors.forename: Rose
authors.initials: R
authors.lastname: Webster
authors.affiliation: Department of Surgery, University of Cincinnati, Cincinnati, Ohio; and.
authors.forename: Sulaiman
authors.initials: S
authors.lastname: Sheriff
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, University of Cincinnati, Cincinnati, Ohio;
authors.forename: Rashma
authors.initials: R
authors.lastname: Faroqui
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, University of Cincinnati, Cincinnati, Ohio;
authors.forename: Faraaz
authors.initials: F
authors.lastname: Siddiqui
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota.
authors.forename: John R
authors.initials: JR
authors.lastname: Hawse
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, University of Cincinnati, Cincinnati, Ohio; Amlalh@uc.edu.
authors.forename: Hassane
authors.initials: H
authors.lastname: Amlal
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D020121:5' Untranslated Regions / Q000235:genetics; D000818:Animals; D002460:Cell Line; D015536:Down-Regulation / Q000235:genetics / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000502:physiology*; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000502:physiology*; D005966:Glucuronidase / Q000235:genetics / Q000502:physiology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D000090265:Klotho Proteins; D051379:Mice; D018345:Mice, Knockout; D010281:Parathyroid Hormone / Q000235:genetics / Q000502:physiology*; D010710:Phosphates / Q000097:blood / Q000652:urine; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D047628:Estrogen Receptor alpha; D010281:Parathyroid Hormone; D010710:Phosphates; C493555:Slc34a1 protein, mouse; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D004958:Estradiol; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: estrogen; hyperphosphatemia; hypophosphatemia; inorganic phosphate; parathyroid hormone; proximal tubule; sex steroids