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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Parathyroid hormone inhibition of Na+/H+ exchanger 3 transcription: Intracellular signaling pathways and transcription factor expression

Full text
Author(s):
Neri, Elida Adalgisa [1] ; Alves Bezerra, Camila Nogueira [1] ; Queiroz-Leite, Gabriella Duarte [1] ; Polidoro, Juliano Zequini [1] ; Reboucas, Nancy Amaral [1]
Total Authors: 5
Affiliation:
[1] Univ Sao Paulo, Dept Physiol & Biophys, Inst Biomed Sci, BR-05508000 Sao Paulo, SP - Brazil
Total Affiliations: 1
Document type: Journal article
Source: Biochemical and Biophysical Research Communications; v. 461, n. 4, p. 582-588, JUN 12 2015.
Web of Science Citations: 1
Abstract

The main transport mechanism of reabsorption of sodium bicarbonate and fluid in the renal proximal tubules involves Na+/H+ exchanger 3 (NHE3), which is acutely and chronically downregulated by parathyroid hormone (PTH). Although PTH is known to exert an inhibitory effect on NHE3 expression and transcription, the molecular mechanisms involved remain unclear. Here, we demonstrated that, in opossum kidney proximal tubule (OKP) cells, PTH-induced inhibition of Nhe3 gene promoter occurs even in the core promoter that controls expression of the reporter gene. We found that inhibition of the protein kinase A (PKA) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways transformed PTH from an inhibitor of promoter activity into an activator of that same activity, as did point mutations in the EGR1, Sp1, and Sp3 binding consensus elements in the promoter. In nuclear extracts of PTH-treated OKP cells, we also observed increased expression of EGR1 mRNA and of some Sp3 isoforms. Electrophoretic mobility shift assay showed a supershift of the -61 to -42-bp probe with an anti-EGR1 antibody in PTH-treated cells, suggesting that EGR1 binding is relevant for the inhibitory activity of PTH. We conclude that PTH-induced inhibition of NHE3 transcription is related to higher EGR1 expression; to EGR1 binding to the proximal and core promoters; and to PICA and JAK/STAT pathway activation. This mechanism might be responsible, at least in part, for lower NHE3 expression and sodium reabsorption in renal proximal tubules in the presence of high PTH levels. (C) 2015 Elsevier Inc. All rights reserved. (AU)

FAPESP's process: 13/23087-4 - Molecular and functional study of membrane transporters
Grantee:Gerhard Malnic
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 08/58287-5 - Molecular and functional study of ion transporters in membranes
Grantee:Gerhard Malnic
Support Opportunities: Research Projects - Thematic Grants