Klotho/fibroblast growth factor 23- and PTH-independent estrogen receptor-α-mediated direct downregulation of NaPi-IIa by estrogen in the mouse kidney

Rose Webster, Sulaiman Sheriff, Rashma Faroqui, Faraaz Siddiqui, John R Hawse, Hassane Amlal

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)F249-F259
JournalAmerican Journal of Physiology - Renal Physiology
Volume311
Issue number2
DOIs
StatePublished - Aug 1 2016

Fingerprint

Parathyroid Hormone
Estrogen Receptors
Estrogens
Down-Regulation
Kidney
Knockout Mice
Hypophosphatemia
3' Untranslated Regions
Open Reading Frames
Eating
Phosphates
Familial Hypophosphatemia
Messenger RNA
Proteins
fibroblast growth factor 23
5' Untranslated Regions
Protein Isoforms
Plasmids
Cell Line
Mutation

Keywords

  • Estrogen
  • Hyperphosphatemia
  • Hypophosphatemia
  • Inorganic phosphate
  • Parathyroid hormone
  • Proximal tubule
  • Sex steroids

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

Klotho/fibroblast growth factor 23- and PTH-independent estrogen receptor-α-mediated direct downregulation of NaPi-IIa by estrogen in the mouse kidney. / Webster, Rose; Sheriff, Sulaiman; Faroqui, Rashma; Siddiqui, Faraaz; Hawse, John R; Amlal, Hassane.

In: American Journal of Physiology - Renal Physiology, Vol. 311, No. 2, 01.08.2016, p. F249-F259.

Research output: Contribution to journalArticle

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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.",
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