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

Thomas, Christie P.; Liu, Kang Z.; Vats, Hemender S.

doi:10.1152/ajprenal.00062.2005

Cited by 34 publications

(20 citation statements)

References 43 publications

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“…10 Collective evidence, thus, strongly suggests that synthetic progestins act differently because of different profiles in the activation of, for example, androgen and glucocorticoid receptors, and it seems likely that some progestins increase vascular injury, whereas others exert rather beneficial effects. 11,39,40 The observation that MPA attenuated the protective effect of 17␤-estradiol in AST rats could be explained either by enhanced mineralocorticoid activity or, alternatively, by inhibition of estrogen action. To discriminate between these mechanisms, we analyzed the cardiovascular phenotype of ovx AST rats on long-term administration of MPA.…”

Section: Discussionmentioning

confidence: 99%

Medroxyprogesterone Acetate But Not Drospirenone Ablates the Protective Function of 17β-Estradiol in Aldosterone Salt-Treated Rats

Arias-Loza

Schäfer

et al. 2006

Hypertension

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Abstract-Controversial results obtained from human and animal studies on the prevention of heart disease by estrogens and progestins warrant a better understanding of nuclear hormone receptor function and interaction. To address this issue and taking into account that effects of synthetic progestins are not only referable to action through the progesterone receptor but may also be mediated by other steroid receptors, we characterized cardiovascular function and inflammatory gene expression in aldosterone salt-treated rats on long-term administration of 17␤-estradiol, medroxyprogesterone acetate, and drospirenone, a new progestogen exhibiting antimineralocorticoid activity. The complex pattern of cardiovascular injury in ovariectomized Wistar rats induced by chronic aldosterone infusion plus a high-salt diet was significantly attenuated in sham-ovariectomized rats and by coadministration of 17␤-estradiol in ovariectomized animals after 8 weeks of continuous treatment. The beneficial role of 17␤-estradiol on blood pressure, cardiac hypertrophy, vascular osteopontin expression, perivascular fibrosis, and impaired NO-dependent relaxation of isolated aortic rings was completely abrogated by coadministration of medroxyprogesterone acetate. In contrast, drospirenone was either neutral or additive to 17␤-estradiol in protecting against aldosterone salt-induced cardiovascular injury and inflammation. The current results support the hypothesis of complex interactions among estrogen, progesterone, glucocorticoid, androgen, and mineralocorticoid receptor signaling in cardiovascular injury and inflammation. Novel progestins, such as drospirenone, confer superior effects compared with medroxyprogesterone acetate in a model of aldosterone-induced heart disease because of its antimineralocorticoid properties.

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Section: Discussionmentioning

confidence: 99%

Medroxyprogesterone Acetate But Not Drospirenone Ablates the Protective Function of 17β-Estradiol in Aldosterone Salt-Treated Rats

Arias-Loza

Schäfer

et al. 2006

Hypertension

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“…mIMCD-3 cells were transfected with a control luciferase vector lacking promoter elements (pGL3) or the αENaC luciferase construct containing 1.3 kbp of the mouse αENaC promoter (23). Cells were cotransfected with either empty expression vector (pCMV-Sport6) or a Per1 expression plasmid (24).…”

Section: Figurementioning

confidence: 99%

The circadian clock protein Period 1 regulates expression of the renal epithelial sodium channel in mice

Gumz¹,

Stow²,

Lynch³

et al. 2009

J. Clin. Invest.

190

187

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The mineralocorticoid aldosterone is a major regulator of sodium transport in target epithelia and contributes to the control of blood pressure and cardiac function. It specifically functions to increase renal absorption of sodium from tubular fluid via regulation of the α subunit of the epithelial sodium channel (αENaC). We previously used microarray technology to identify the immediate transcriptional targets of aldosterone in a mouse inner medullary collecting duct cell line and found that the transcript induced to the greatest extent was the circadian clock gene Period 1. Here, we investigated the role of Period 1 in mediating the downstream effects of aldosterone in renal cells. Aldosterone treatment stimulated expression of Period 1 (Per1) mRNA in renal collecting duct cell lines and in the rodent kidney. RNA silencing of Period 1 dramatically decreased expression of mRNA encoding αENaC in the presence or absence of aldosterone. Furthermore, expression of αENaC-encoding mRNA was attenuated in the renal medulla of mice with disruption of the Per1 gene, and these mice exhibited increased urinary sodium excretion. Renal αENaC-encoding mRNA was expressed in an apparent circadian pattern, and this pattern was dramatically altered in mice lacking functional Period genes. These results suggest a role for Period 1 in the regulation of the renal epithelial sodium channel and more broadly implicate the circadian clock in control of sodium balance.

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“…Alternative mechanisms that could explain the further deterioration of LV function in rats treated with MPA plus E2 may have played a role. Importantly, synthetic progestins such as MPA bind and transactivate not only their cognate receptor but also the MR, the AR, and the GR (Sitruk-Ware 2004;Schindler et al 2003;Thomas, Liu, and Vats 2006). Excessive, liganddependent MR activation has repeatedly been shown to impair cardiac remodeling and chronic HF.…”

Section: Discussionmentioning

confidence: 99%

Medroxyprogesterone Acetate Aggravates Oxidative Stress and Left Ventricular Dysfunction in Rats with Chronic Myocardial Infarction

Arias-Loza

Frantz

et al. 2011

Toxicol Pathol

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The role of estrogens during myocardial ischemia has been extensively studied. However, effects of a standard hormone replacement therapy including 17b-estradiol (E2) combined with medroxyprogesterone acetate (MPA) have not been assessed, and this combination could have contributed to the negative outcomes of the clinical studies on hormone replacement. We hypothesized that adding MPA to an E2 treatment would aggravate chronic heart failure after experimental myocardial infarction (MI). To address this issue, we evaluated clinical signs of heart failure as well as left ventricular (LV) dysfunction and remodeling in ovariectomized rats subjected to chronic MI receiving E2 or E2 plus MPA. After eight weeks MI E2 showed no effects. Adding MPA to E2 aggravated LV remodeling and dysfunction as judged by increased heart weight, elevated myocyte cross-sectional areas, increased elevated left ventricle end diastolic pressure, and decreased LV fractional shortening. Impaired LV function in rats receiving MPA plus E2 was associated with increased cardiac reactive oxygen species generation and myocardial expression levels of NADPH oxidase subunits. These results support the interpretation that adding MPA to an E2 treatment complicates cardiovascular injury damage post-MI and therefore contributes to explain the adverse outcome of prospective clinical studies.

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

Abstract: Thomas, Christie P., Kang Z. Liu, and Hemender S. Vats. Medroxyprogesterone acetate binds the glucocorticoid receptor to stimulate ␣-ENaC and sgk1 expression in renal collecting duct epithelia.

Cited by 34 publications

References 43 publications

Medroxyprogesterone Acetate But Not Drospirenone Ablates the Protective Function of 17β-Estradiol in Aldosterone Salt-Treated Rats

Medroxyprogesterone Acetate But Not Drospirenone Ablates the Protective Function of 17β-Estradiol in Aldosterone Salt-Treated Rats

The circadian clock protein Period 1 regulates expression of the renal epithelial sodium channel in mice

Medroxyprogesterone Acetate Aggravates Oxidative Stress and Left Ventricular Dysfunction in Rats with Chronic Myocardial Infarction

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