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

Estrogen receptor alpha, not beta, is the primary mediator of the attenuating effects of estrogens on body weight gain.

Sex Differences in Estrogen Regulation of Renal 11b-Hydroxysteroid Dehydrogenases

Darren M. Roesch, Ph.D.


Renal FunctionCardiovascular FunctionRenal DiseaseCardiovascular DiseaseLIFE EXPECTANCY

Sex ChromosomesGonadal HormonesMechanisms?


AldosteroneCortisolAdrenal Gland

InactiveDo sex steroids Regulate 11bHSD2?Estrogen increases expression and activity of 11b-HSD2Estrogen prevents activation of MR by Cortisol


Is there a sex difference in estrogen regulation of renal 11b-HSD2 Activity?

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.

11bHSD2 Protein Abundance by Western Blot.

11b-HSD2 ActivityMale





+E2Under the influence of estrogen, female mineralocorticoid receptorsare primarily regulated by cortisol and basal MR activity is increased.Hypothesis

When estrogens are high, females may bemore sensitive to stress-associated hypertensionand cardiovascular diseaseObesity!Effects of Estrogen on Resting Plasma ParametersOVXESTRADIOLPRA(ng/ml/hr)97.2 12.797.018.2Na+ (mmol/L)136.00.5139.00.5 K+ (mmol/L) Osmolality (mmol/L)28332862Hematocrit(%)371342Protein(g/100ml) 16Does Estrogen Enhance Mineralocorticoid Activity in the Kidney?

17Adrenalectomy Abolishes the Effect of Estrogen on K

18Estrogen Decreases AT1 Receptors

19Estrogen Attenuates Angiotensin-Induced Aldosterone Secretion

20Adrenal Angiotensin Receptor Density is Regulated by Plasma Potassium

21The Effects of Estrogen on Adrenal AT1R Could be Regulated by Estrogens Effects on K


corticosteronePlasma [K+]+E2AdrenalAT1R-E2stimulatedaldosteroneangiotensin IIConclusions11bHSD2 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.

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.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 NKFGeorgetowns Intramural Research Grant ProgramKorea Research Institute of Chemical Technology