Medroxyprogesterone acetate binds the glucocorticoid receptor to stimulate alpha-ENaC and sgk1 expression in renal collecting duct epithelia

Christie P Thomas; Kang Z Liu; Hemender S Vats

doi:10.1152/ajprenal.00062.2005

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Medroxyprogesterone acetate binds the glucocorticoid receptor to stimulate alpha-ENaC and sgk1 expression in renal collecting duct epithelia

Journal article

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Peer reviewed

Medroxyprogesterone acetate binds the glucocorticoid receptor to stimulate alpha-ENaC and sgk1 expression in renal collecting duct epithelia

Christie P Thomas, Kang Z Liu and Hemender S Vats

American journal of physiology. Renal physiology, Vol.290(2), pp.F306-312

02/2006

DOI: 10.1152/ajprenal.00062.2005

PMID: 16189295

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Abstract

Medroxyprogesterone acetate (MPA), a widely used synthetic progestational contraceptive, occasionally leads to Cushingoid side effects such as hypertension, fluid retention, and centripetal obesity. We investigated the effect of MPA on classic mineralocorticoid target genes, alpha-epithelial Na channel (ENaC) and sgk1, in the collecting duct. In adrenalectomized mice, aldosterone, dexamethasone, and MPA increased alpha-ENaC mRNA levels in kidney cortex. MPA and dexamethasone, but not progesterone, dose dependently increased alpha-ENaC and sgk1 mRNA in M-1 and in Madin-Darby canine kidney-C7 cells, both collecting duct cell lines. The stimulatory effect of MPA and dexamethasone on alpha-ENaC expression was inhibited by RU-38486, a combined glucocorticoid receptor (GR) and progesterone receptor (PR) antagonist, but not by Org31710, a pure PR antagonist. MPA and dexamethasone dose dependently increased alpha-ENaC promoter-driven luciferase activity in M-1 cells, which was not inhibited by Org31710, indicating that MPA regulates alpha-ENaC in a PR-independent manner. When tested in HT29 cells, MPA could only stimulate alpha-ENaC-driven reporter activity when GR was coexpressed, confirming the requirement for functional GR in the transcriptional effect of MPA. The activation of steroid receptors such as GR can explain the apparent glucocorticoid effects of MPA, independent of PR activation.

Cell Line

Receptors, Glucocorticoid - antagonists & inhibitors

Kidney Cortex - metabolism

Humans

Mice, Inbred C57BL

Medroxyprogesterone Acetate - pharmacology

Male

Receptors, Glucocorticoid - metabolism

Medroxyprogesterone Acetate - metabolism

Ribonucleases - metabolism

Dose-Response Relationship, Drug

Epithelial Sodium Channels

Immediate-Early Proteins - metabolism

Kidney Tubules, Collecting - metabolism

Animals

Transfection

Dogs

Kidney Medulla - metabolism

Sodium Channels - metabolism

5' Flanking Region

Mice

Sodium Channels - genetics

Protein-Serine-Threonine Kinases - metabolism

Details

Title: Subtitle: Medroxyprogesterone acetate binds the glucocorticoid receptor to stimulate alpha-ENaC and sgk1 expression in renal collecting duct epithelia
Creators: Christie P Thomas - Division of Nephrology, Department of Internal Medicine, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242-1081, USA. christie-thomas@uiowa.edu
Kang Z Liu
Hemender S Vats
Resource Type: Journal article
Publication Details: American journal of physiology. Renal physiology, Vol.290(2), pp.F306-312
DOI: 10.1152/ajprenal.00062.2005
PMID: 16189295
NLM abbreviation: Am J Physiol Renal Physiol
ISSN: 1931-857X
eISSN: 1522-1466
Publisher: United States
Grant note: DK-54348 / NIDDK NIH HHS HL-71664 / NHLBI NIH HHS R01 DK054348 / NIDDK NIH HHS R01 HL071664 / NHLBI NIH HHS
Language: English
Date published: 02/2006
Academic Unit: Stead Family Department of Pediatrics; Obstetrics and Gynecology; Internal Medicine
Record Identifier: 9983986081602771

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