| First Author | Webster R | Year | 2016 |
| Journal | Am J Physiol Renal Physiol | Volume | 311 |
| Issue | 2 | Pages | F249-59 |
| PubMed ID | 27194721 | Mgi Jnum | J:280532 |
| Mgi Id | MGI:6369576 | Doi | 10.1152/ajprenal.00542.2015 |
| Citation | Webster R, et al. (2016) Klotho/fibroblast growth factor 23- and PTH-independent estrogen receptor-alpha-mediated direct downregulation of NaPi-IIa by estrogen in the mouse kidney. Am J Physiol Renal Physiol 311(2):F249-59 |
| abstractText | 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 (ERalpha and ERbeta) 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 ERalpha or ERbeta or Klotho and their wild type (WT) using balance studies in metabolic cages. Estrogen treatment of WT and ERbeta 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 ERalpha 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 ERalpha and ERbeta 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 ERalpha. 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. |
