There are profound sex differences in renal function that contribute to sex differences in cardiovascular function, the risk for hypertension, and subsequent development of cardiovascular disease. The effects of estrogens on cardiovascular function are controversial. Some studies suggest estrogens are cardioprotective and others studies suggest estrogens increase cardiovascular risk. Adrenocortical steroids such as the stress hormone, corticosterone, and the mineralocorticoid, aldosterone, can bind and stimulate renal salt reabsorption via the mineralocorticoid receptor (MR). Because corticosterone circulates at much higher levels and has a higher affinity for the MR than aldosterone, it might be expected that all activity at MR would be through corticosterone. However, the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD-2) inactivates corticosterone and protects MR from activation by circulating glucocorticoids. We have found that estrogen, a hormone that also increases circulating levels of corticosterone, increases levels of 11β-HSD-2 in males but not females. Therefore, we predict that estrogen increases stress hormone (corticosterone)-mediated salt reabsorption in females more than in males. Since many of the animal studies that predict cardioprotection by estrogen have been conducted in males, and most of the human clinical studies are conducted in females, we hypothesize that a sex/gender difference in renal 11β-HSD-2 responsiveness to estrogen may contribute to the apparent controversy over the effectiveness of estrogen in protecting against cardiovascular disease. Future studies in this laboratory will determine the mechanism of the sex/gender difference in the regulation of 11β-HSD-2 so that increases in 11β-HSD-2 activity might be pharmacologically induced in order to prevent estrogen and stress-associated increases in renal salt reabsorption and the associated increases in blood pressure and the risk for cardiovascular disease.

1. Sex Differences in Estrogen
Regulation of Renal 11b-
Hydroxysteroid Dehydrogenases
Darren M. Roesch, Ph.D.

2. Renal Function
Cardiovascular Function
Renal Disease
Cardiovascular Disease

3. Sex Chromosomes
Mechanisms?
Gonadal Hormones

5. Adrenal Gland
Aldosterone
Cortisol

7. Do sex steroids Regulate 11bHSD2?
Gomez-Sanchez
Estrogen increases expression and activity of 11b-HSD2
Estrogen prevents activation of MR by Cortisol

9. Methods
Gonadectomized 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.

10. 11bHSD2 Protein Abundance by Western Blot.
7 A
DMSO
6
E2
5
Absorbence
4
3 B B
B
2
1
0
Female Male

12. 11b-HSD2 Activity
*
Male Female

13. +E2

14. +E2

15. Hypothesis
Under the influence of estrogen, female mineralocorticoid receptors
are primarily regulated by cortisol and basal MR activity is increased.
When estrogens are high, females may be
more sensitive to stress-associated hypertension
and cardiovascular disease
Obesity!

16. Effects of Estrogen on Resting Plasma Parameters
OVX ESTRADIOL
PRA 97.2 ±12.7 97.0±18.2
(ng/ml/hr)
139.0±0.5 
Na+ 136.0±0.5
(mmol/L)
4.6±0.2 
K+ 6.2±0.3
(mmol/L)
Osmolality 283±3 286±2
(mmol/L)
Hematocrit 37±1 34±2
(%)
6.6±0.2 
Protein 5.3±0.2
(g/100ml)

17. Does Estrogen Enhance Mineralocorticoid Activity in
the Kidney?

18. Adrenalectomy Abolishes
the Effect of Estrogen on
K

19. Estrogen Decreases AT1
Receptors

20. Estrogen Attenuates Angiotensin-Induced Aldosterone Secretion
3000
A ld o s te ro n e (p g /m l)
2500
2000 -E 2
1500
1000
* +E2
500 -E 2
0 +E2
0 30 60 90 120
T im e (m in )

21. Adrenal Angiotensin Receptor Density is Regulated by
Plasma Potassium

22. The Effects of Estrogen
on Adrenal AT1R Could
be Regulated by
Estrogen’s Effects on K

23. stimulated angiotensin II
aldosterone
Adrenal
AT1R
Plasma [K+]
-E2
+E2 corticosterone

24. Conclusions
11bHSD2 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 mediated
hypertension when estrogen levels are high.

25. 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.

26. Acknowledgements
Joseph G. Verbalis, M.D.
Kathryn Sandberg, Ph.D.
Wei Zheng, M.D.
Min Shi, 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 Program
Korea Research Institute of Chemical Technology