Open AccessEstrogen receptor α (ERα) indirectly induces transcription of human renal organic anion transporter 1 (OAT1)
Author(s) -
Euteneuer Anna M.,
SeegerNukpezah Tamina,
Nolte Hendrik,
Henjakovic Maja
Publication year - 2019
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.14229
Subject(s) - organic anion transporter 1 , transcription factor , estrogen receptor , estrogen , biology , cancer research , endocrinology , microbiology and biotechnology , chemistry , medicine , transporter , biochemistry , gene , cancer , breast cancer
Organic anion transporter 1 (OAT1) is a polyspecific transport protein located in the basolateral membrane of renal proximal tubule cells. OAT1 plays a pivotal role in drug clearance. Adverse drug reactions (ADR) are observed more frequently in women than in men, especially ADR are higher in women for drugs which are known interactors of OAT1. Sex‐dependent expression of Oat1 has been observed in rodents with a tendency to male‐dominant expression. This study aims at elucidating the transcriptional regulation of human OAT1 and tests the effect of estrogen receptor α (ERα). Promoter activation of OAT1 was assessed by luciferase assays carried out by Opossum kidney (OK) cells, transiently transfected with promoter constructs of human OAT1 and expression vectors for ERα and exposed to 100 nmol/L 17β‐estradiol. Furthermore, a transcription factor array and proteomic analysis was performed to identify estrogen‐induced transcription factors. Human OAT1 was significantly activated by ligand activated ERα. However, activation occurred without a direct interaction of ERα with the OAT1 promoter. Our data rather show an activation of the transcription factors CCAAT‐box‐binding transcription factor (CBF) and heterogeneous nuclear ribonucleoprotein K (HNRNPK) by ERα, which in turn bind and initiate OAT1 promoter activity. Herewith, we provide novel evidence of estrogen‐dependent, transcriptional regulation of polyspecific drug transporters including the estrogen‐induced transcription factors CBF and HNRNPK.