Sex Differences in Estrogen

Regulation of Renal 11b-

Hydroxysteroid Dehydrogenases

Darren M. Roesch, Ph.D.

Renal Function

Cardiovascular Function

Renal Disease

Cardiovascular Disease

Sex Chromosomes

Gonadal Hormones

Mechanisms?

Aldosterone

Cortisol

Adrenal Gland

Do sex steroids Regulate 11bHSD2?

Estrogen increases expression and activity of 11b-HSD2

Estrogen prevents activation of MR by Cortisol

Gomez-Sanchez

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.

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.

11b-HSD2 Activity

Male Female

*

+E2

+E2

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!

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

Does Estrogen Enhance Mineralocorticoid Activity in

the Kidney?

Adrenalectomy Abolishes

the Effect of Estrogen on

K

Estrogen Decreases AT1

Receptors

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

Adrenal Angiotensin Receptor Density is Regulated by

Plasma Potassium

The Effects of Estrogen

on Adrenal AT1R Could

be Regulated by

Estrogen’s Effects on K

corticosterone

Plasma [K+]

+E2

AdrenalAT1R

-E2

stimulated

aldosterone

angiotensin II

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.

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 NKF

Georgetown’s Intramural Research Grant ProgramKorea Research Institute of Chemical Technology