Sex Differences in Estrogen Regulation of Renal 11β-Hydroxysteroid Dehydrogenases
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Transcript of Sex Differences in Estrogen Regulation of Renal 11β-Hydroxysteroid Dehydrogenases
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Sex Differences in Estrogen
Regulation of Renal 11b-
Hydroxysteroid Dehydrogenases
Darren M. Roesch, Ph.D.
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Renal Function
Cardiovascular Function
Renal Disease
Cardiovascular Disease
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Sex Chromosomes
Gonadal Hormones
Mechanisms?
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Aldosterone
Cortisol
Adrenal Gland
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Do sex steroids Regulate 11bHSD2?
Estrogen increases expression and activity of 11b-HSD2
Estrogen prevents activation of MR by Cortisol
Gomez-Sanchez
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MethodsGonadectomized male and female rats.
Injections of estradiol valerate (5 mg) every four days.
11bHSD2 protein abundance measured by Western blot.
11bHSD2 Activity measured by in vitro assay and TLC.
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0
1
2
3
4
5
6
7 A
B BB
DMSO
E2
Female Male
Ab
so
rben
ce
11bHSD2 Protein Abundance by Western Blot.
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11b-HSD2 Activity
Male Female
*
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+E2
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+E2
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Under the influence of estrogen, female mineralocorticoid receptors
are primarily regulated by cortisol and basal MR activity is increased.
Hypothesis
When estrogens are high, females may be
more sensitive to stress-associated hypertension
and cardiovascular disease
Obesity!
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Effects of Estrogen on Resting Plasma Parameters
OVX ESTRADIOL
PRA(ng/ml/hr)
97.2 ±12.7 97.0±18.2
Na+
(mmol/L)
136.0±0.5139.0±0.5
K+
(mmol/L)
6.2±0.34.6±0.2
Osmolality (mmol/L)
283±3 286±2
Hematocrit(%)
37±1 34±2
Protein(g/100ml)
5.3±0.26.6±0.2
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Does Estrogen Enhance Mineralocorticoid Activity in
the Kidney?
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Adrenalectomy Abolishes
the Effect of Estrogen on
K
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Estrogen Decreases AT1
Receptors
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Estrogen Attenuates Angiotensin-Induced Aldosterone Secretion
Tim e (m in)
0 30 60 90 120
Ald
os
tero
ne
(p
g/m
l)
0
500
1000
1500
2000
2500
3000
*
-E2
+E2
+E2
-E2
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Adrenal Angiotensin Receptor Density is Regulated by
Plasma Potassium
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The Effects of Estrogen
on Adrenal AT1R Could
be Regulated by
Estrogen’s Effects on K
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corticosterone
Plasma [K+]
+E2
AdrenalAT1R
-E2
stimulated
aldosterone
angiotensin II
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Conclusions11bHSD2 activity is increased by estrogens in males but not females.
Estrogen increases mineralocorticoid receptor activity in females.
Likely due to increased corticosterone activity at MR.
Females may be more sensitive to stress and mineralocorticoid receptor mediatedhypertension when estrogen levels are high.
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Determine the mechanism of the sex difference in estrogen regulation of 11bHSD2.
Determine the role of estrogen sensitivity in obesity.
Determine the interaction between estrogen and stress in obesity-associated renal and cardiovascular disease.
Prevent stress-induced renal and cardiovascular complications in lean and obese patients.
Harness the power of estrogens to prevent obesity.
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Acknowledgements
Min Shi, M.D.
Joseph G. Verbalis, M.D.
Kathryn Sandberg, Ph.D.Wei Zheng, M.D.Hong Ji, M.D.Ying Tian, M.D.Carolyn Ecelbarger, Ph.D.Christine Maric, Ph.D.
NIA DC Chapter of the NKF
Georgetown’s Intramural Research Grant ProgramKorea Research Institute of Chemical Technology