Medroxyprogesterone acetate binds the glucocorticoid receptor to stimulate alpha-ENaC and sgk1 expression in renal collecting duct epithelia.
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.
Thomas
Christie P
CP
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
Liu
Kang Z
KZ
Vats
Hemender S
HS
D024506:5' Flanking Region; D000818:Animals; D002460:Cell Line; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D053503:Epithelial Sodium Channels; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D007672:Kidney Cortex / Q000378:metabolism; D007679:Kidney Medulla / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000378:metabolism*; D008297:Male; D017258:Medroxyprogesterone Acetate / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012260:Ribonucleases / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D000099184:Serum-Glucocorticoid Regulated Kinases
D053503:Epithelial Sodium Channels; D017874:Immediate-Early Proteins; D017258:Medroxyprogesterone Acetate; D017346:Protein Serine-Threonine Kinases; D011965:Receptors, Glucocorticoid; D012260:Ribonucleases; D015222:Sodium Channels; D000099184:Serum-Glucocorticoid Regulated Kinases