Sex Steroids and Renal Disease
Lessons From Animal Studies
Licy L. Yanes, Julio C. Sartori-Valinotti, Jane F. Reckelhoff
higher than ER␣ or GPR30, and 17␤-estradiol downregulated
ER␣, ER␤, and GPR30.10
Estradiol is usually thought to be renoprotective. For
example, in cultured mesangial cells, 17␤-estradiol inhibits
apoptosis and transforming growth factor (TGF)-␤ activity
and expression.11 In addition, estradiol is antiinflammatory.12–14 However, with low nitric oxide (NO) and high
angiotensin (Ang) II, estradiol exacerbated renal injury via
upregulation of renal AT1 receptor expression.15 In addition,
in women, oral contraceptives increase in BP and albumin
excretion,16 and occasionally result in hypertension17 and
biopsy-proven renal damage in the absence of primary renal
disease.18
The roles of the ER subtypes in renal function or injury
have been studied mainly by using ER␣ and ER␤ knockout
(KO) mice. ER␣ is mainly responsible for gene regulation
because 10 000 genes were upregulated in kidneys of wildtype (WT) and ␤ERKO mice with estradiol.19 ␤ERKO mice
become hypertensive with aging, and males have higher BP,20
but both male and female are resistant to age-related glomerular sclerosis, suggesting that renal injury/disease does mediate the hypertension. ␣ERKO males are also resistant to
age-related glomerular sclerosis, but females exhibit both
albuminuria and glomerular sclerosis. Ovx prevents glomerulosclerosis in female ␣ERKO, not attributable to the reduction in estradiol or progesterone but to reduction in testosterone.21 ER␤ does provide protection in ischemia/reperfusion
injury of hearts (eg, smaller infarct size) in ␣ERKO females,
but not males.22 However, streptozotocin-diabetic ␣ERKO
females developed higher TGF␤ expression than WT,23
suggesting that ER␤ may play a role in diabetic neprhopathy.
ER␣ and ER␤ are present in endothelial cells and vascular
smooth muscle cells, but the expression is gender- and
vascular bed– dependent.6,7 Similarly, the effect of estradiol
on vasodilation is dependent on the vascular bed studied. For
example, estradiol-mediated vasodilation attributable to nitric
oxide (NO), via endothelial NO synthase (eNOS), was absent
in femoral and carotid arteries from both ␣ERKO and
␤ERKO mice.24 This is consistent with previous studies
showing that basal eNOS activity was reduced in ␣ERKO
E
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pidemiological studies have shown that male sex is an
independent risk factor for the development and progression of renal disease, and men progress to end stage renal
disease (ESRD) faster than premenopausal women in such
diseases as autoimmune glomerulonephritis, hypertensive
glomerulosclerosis, and polycystic kidney disease.1–3 Although the age-related decline in renal function is also faster
in men, women become more susceptible to renal diseases
after menopause.4 Insight from in vitro studies and animal
models suggest that sex steroids play pivotal roles in modifying the progression to ESRD. Because there is a paucity of
data in humans showing the mechanisms by which sex
steroids impact renal disease, most of the studies discussed
this review will be in animals, mainly rats. Furthermore,
determining the roles of sex steroids in various diseases has
been done using gonedectomized animals; however, although
gonadectomy removes more than sex steroids and most
studies only replace the sex steroid of interest, these are still
the best studies in which to evaluate mechanisms responsible
for sex differences in renal disease. Studies in postmenopausal women will also be kept to a minimum in this review
because it is likely that sex steroids change action with aging,
as suggested by the Women’s Health Initiative study.
Estradiol and the Kidney
Estrogen receptors (ER) are present in the kidney, although
their localization in nephron segments has not been fully
elucidated. Mesangial cells contain both ER␣ and ER␤,5 as
do endothelium and vascular smooth muscle cells.5–7
Whether the newly described transmembrane estrogen receptor, GPR30,8 is present in kidneys has not been determined.
Ovariectomy (ovx) of Dahl salt sensitive rats (DS) caused
decreases in ER␣ but increases in ER␤ expression in the renal
cortex and medulla,9 whereas ovx in salt resistant (DR) rats
caused decreases in cortical and increases in medullary ER␣,
and increases in ER␤. In addition, estradiol replacement
returned ER␤ expression to preovx levels in both DS and DR,
but had no effect on ER␣. In contrast, in internal mammary
arteries from humans, ER␤ mRNA expression was 10-fold
Received December 3, 2007; first decision December 28, 2007; revision accepted January 9, 2008.
From the Department of Physiology and Biophysics, The Center for Excellence in Cardiovascular–Renal Research, University of Mississippi Medical
Center, Jackson.
This paper was sent to Richard J. Roman, associate editor, for review by expert referees, editorial decision, and final disposition.
Correspondence to Jane F. Reckelhoff, PhD, Professor, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500
North State Street, Jackson, MS 39216-4505. E-mail [email protected]
(Hypertension. 2008;51:976-981.)
© 2008 American Heart Association, Inc.
Hypertension is available at http://hypertension.ahajournals.org
DOI: 10.1161/HYPERTENSIONAHA.107.105767
976
Yanes et al
mice.25 In contrast, Al Zubair and colleagues reported that
ER␤ agonist caused greater relaxation of female rat mesenteric arteries than did ER␣ agonist.26 However, both agonists
had similar vasodilator effects in males.
Progesterone and the Kidney
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Progesterone receptors have been found mainly in distal
tubule cells, although they are present in cortex and medulla
of males and females.27 The role that progesterone plays in
physiology and pathology of the kidney is not clear. Progesterone has a high affinity for the mineralocorticoid receptor
(MR) and can act as an MR antagonist. In rats with DOCAsalt hypertension, mediated by the MR, progesterone alone,
the combination of progesterone and estrogen, but not estrogen alone, attenuated renal damage and preproendothelin
mRNA expression,28 suggesting that treatment with progesterone may have acted as an MR antagonist in this study.
However, progesterone can be degraded in the kidney to
metabolites that have lower affinity for the MR.29 In contrast,
in ovx rats with 5/6 renal ablation, estradiol protected against
proteinuria and glomerulsclerosis, but rats treated with
estradiol⫹progesterone exhibited the same renal damage as
vehicle-treated rats.30 In this case then progesterone promoted
renal injury. In another study, early ovx caused a reduction in
renal functional reserve and fractional proximal tubular fluid
output in middle-aged rats (13 months) that was reversed with
estradiol alone or estradiol and progesterone.31 Progesterone
may also increase sodium reabsorption independent of its
effect on the MR, because progesterone alone moderately
increased ENaC activity in cortical collecting duct cells, but
progesterone and low-dose estradiol increased ENaC activity
by 2-fold, whereas high-dose estradiol almost completely
inhibited ENaC activity.32 Testosterone has also been shown
to increase ENaC expression in the kidney,33 and progesterone can transactivate the androgen receptor.34 Furthermore,
progesterone can be metabolized to both testosterone and
dihydrotestosterone in the kidney.35 Therefore, some of the
effects of progesterone on the kidney may be attributable to
its androgenic effects.
Testosterone and the Kidney
The kidney can synthesize testosterone and dihydrotestosterone because it contains the cytochrome P450 enzymes that
are necessary.35 Similar to the estradiol receptors, the complete nephron localization for the androgen receptor (AR) has
not been elucidated. Mesangial cells, glomeruli, proximal
tubules, and cortical collecting ducts contain AR.21,36 Treatment of normotensive rats with dihydrotestosterone increases
proximal sodium reabsorption, via an Ang II–mediated mechanism, and BP,37 but neither GFR nor AT1 receptor binding
was affected. This is in contrast to acute infusion of testosterone that increases GFR and renal plasma flow and reduces
renal vascular resistance (Reckelhoff, unpublished results,
1998). Therefore, androgens have both chronic and acute
effects on the kidney.
Male rats experience a more rapid reduction in GFR and
more renal injury with age than females.37– 40 However, the
reduction in GFR cannot be fully accounted for by the level
of glomerular injury found in the kidneys, suggesting that
Sex and Renal Disease
977
aging is a state of renal vasoconstriction. For example, in
male normotensive rats, aged 20 to 22 months, GFR was
reduced by 50% compared to young males and yet only 20%
of their glomeruli exhibited sclerosis.38 In aging male SHR,
GFR was reduced by 30% and renal vascular resistance was
increased 30%, whereas less than 5% cof glomeruli had
sclerosis.39 Castration of aging SHR and Munich Wistar rats
prevents reductions in GFR and glomerular injury.37,39 In
addition, castration prevents the increase in renal vascular
resistance. Castration of male rats with renal-wrap hypertension also attenuated the glomerular injury and proteinuria.41
When castrated rats or ovx females with renal-wrap hypertension were treated with dihydrotestosterone, glomerular
injury was exacerbated.
Testosterone can mediate renal injury in females. Testosterone supplements increased expression of AR and TGF-␤1
in glomeruli of ovx B6 mice,21 and AR antagonism protects
against renal injury in female TGR(mREN2)27.42 The concept that androgens may also be harmful to kidneys of
females is important because postmenopausal women may
produce more androgens as they age.35
Plasma testosterone levels are decreased in most men
with aging and other chronic diseases, such as CKD.43
Thus many investigators believe that renal disease is
independent of androgens. However, because the kidney is
capable of synthesizing androgens,35 it is not clear whether
reductions in plasma testosterone reflect similar changes in
renal testosterone.
Diabetes, Hyperlipidemia, and Sex Steroids
Before puberty, renal complications of diabetes (DM) are
rare, but the incidence of renal disease in DM sharply
increases after puberty.44 In a large clinical trial of 27 805
individuals with type 1 DM, male sex was an independent
risk factor associated with the development of CKD.45 Other
studies have also shown that the “female protective factor” is
lost in the presence of diabetes,46 perhaps because of a
decrease in plasma estradiol as found in female rats with
streptozotocin-induced type 1 DM.47 17␤-Estradiol replacement reversed renal fibrosis.48 Similarly, in hypertensive type
II DM, postmenopausal women, 17␤-estradiol replacement
was also shown to be protective against renal disease.49
Metabolic syndrome, including insulin resistance, type II
DM, and dyslipidemia, constitutes a major risk factor for
developing CKD. In a recent study, a positive correlation
between the number of components of metabolic syndrome
and the incidence of CKD was found.50 Of interest, no gender
difference in the incidence of CKD was reported, with
women having the same incidence as men.50 In Zucker (fa/fa)
rats, a model of type 2DM and hyperlipidemia, there are
gender differences in vascular reactivity, where the males
exhibit an impaired response to vasoconstrictors and to
endothelial-mediated vasodilation.51 Males exhibited a paradoxical decrease in vascular resistance in response to
thromboxane agonist and blunting of the response to Ang II.
In addition, Zucker males exhibited a blunted vasodilatory
response to acetylcholine and a blunted vasoconstrictor response to nitro-L-arginine methyl ester (L-NAME), inhibitor
of NOS. Castration improved vascular responses.52 However,
978
Hypertension
April 2008 Part II
in aging Zucker rats, ESRD was found to be the major cause
of mortality, and a gender difference was not observed
(males: 91.1%, females: 93.3%).53 Although it is possible that
a reduction in estradiol could have played a role in lack of
protection in females, administration of estradiol to ovx
Zucker rats impaired renal function further and led to profound glomerulosclerosis.54 These data suggest that in presence of metabolic syndrome, type II DM, or dyslipidemia, the
effects of sex steroids on renal disease are unpredictable.
Hypertension and Sex Steroids
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Hypertension is more prevalent and more severe in men than
women.55 However, the sex difference in BP is lost after
menopause. Sex differences in renal injury in humans follow
the BP; ie, hypertensive men have a higher incidence of
ESRD than women.2 The mechanisms are not clear, but
changes in sex steroid–mediated differences in glomerular
capillary pressure (PGC) may play a role. Glomerular hypertension is a key factor in the pathogenesis of progressive
glomerulosclerosis and renal failure, independent of the
initial insult.56,57 For example, in response to Ang II infusion,
men and women exhibited similar increases in BP and decline
in effective renal plasma flow (ERPF),58 whereas GFR was
maintained only in men, resulting in an increase of filtration
fraction (FF). In women, GFR declined in parallel with
ERPF, and thus there was little increase in FF,58 which is an
indication of PGC. Thus PGC in men likely increased more in
response to Ang II than in women, which if sustained over
time, would lead to greater glomerular injury in men.
Hypertension in animal models is associated with the renal
injury, although the extent depends on the age, the model, and
the experimental design. In the SHR, BP is higher in males,
but renal injury only occurs with aging, but PGC is elevated in
males by age 9 months, before any renal damage.59 Although
BP increases in female SHR after cessation of estrous cycling
to levels not different or even higher than males,60 females
exhibit little glomerulosclerosis compared to males.61
Whether PGC is increased in aged female SHR has not been
determined.
Whether and how sex steroids could affect PGC is not clear,
however. Testosterone has been shown to have modulating
effects on calcium channels. For example, chronic testosterone causes an increase in T type calcium currents.62 Alternatively, L-type calcium currents are blocked by testosterone.63
Feng and colleagues reported that both L- and T-type calcium
channels are present in afferent and efferent arterioles.64 It is
possible that androgens could modulate these calcium currents leading to preglomerular vasodilation leading to an
increase in PGC. Alternatively, estradiol could have the opposite effect on calcium channels and thus protect glomeruli
from increased transmission of the systemic BP, protecting
against increased PGC.
Sex Steroids and Renin-Angiotensin System
Inhibition of the renin-angiotensin system delays the progression of diabetic and nondiabetic renal diseases.65 Testosterone
increases proximal sodium reabsorption via Ang II–mediated
mechanisms37 and increases intrarenal angiotensinogen expression.66,67 If renin does not work at its Vmax, as in humans
and rats, an increase in renin substrate would cause an
increase in Ang II production. Testosterone could promote
renal injury by a hemodynamic mechanism in which it
stimulates Ang II production, leading to increases in sodium
reabsorption in the proximal tubule with a concomitant
reduction of sodium reaching the macula densa, resulting in a
decrease in glomerular afferent resistance (compared to
females) allowing greater transmission of systemic BP to the
glomerular capillary.
Estrogen may protect against renal injury via its effects on
components of the renin-angiotensin system. Estrogen reduces the number of AT1 receptors in many tissues, including
the kidney, and attenuates tissue responsiveness to Ang
II.68 –71 Estrogen increases angiotensinogen levels, mainly in
the liver,71 but appears to decrease plasma renin activity.
However, the lack of protection from primary cardiovascular
events with estrogen replacement found in the Women’s
Health Initiative (WHI) study72 suggests that changes in the
estrogen responsiveness occur after menopause. Whether the
changes in estrogen responsiveness with age are attributable
to changes in expression/intracellular signaling/transcription
activation of the ERs or other mechanisms remain to be
determined.
Sex Steroids and Endothelin
There is a paucity of studies regarding the interaction among
sex hormones, the endothelin system, and renal disease. In
female-to-male transsexuals, testosterone treatment increases
plasma endothelin levels.73 In DOCA-salt rats, renal injury
associated with ovx in females is ameliorated by endothelin
(ETA) receptor antagonism.28 After warm ischemia, the early
recovery of renal blood flow is delayed in male rats compared
to females, due to a greater increase in renal vascular
resistance in males, likely mediated in part by increased
endothelin, because preproendothelin mRNA was elevated in
kidneys of males but not females.74 In uninephrectomized
spontaneously hypertensive-stroke prone rats (SHRsp), ovx
females exhibited significantly greater glomerular damage
and greater endothelin expression than estradiol-treated
animals.75
Ang II has been shown to increase expression of preproendothelin in the kidney.76 Because androgens increase angiotensinogen and plasma renin activity, it is possible that
androgens could increase Ang II leading to increased endothelin and subsequent renal injury. Alternatively, because
estradiol can downregulate AT1 receptor expression, estrogen
should prevent the increase in endothelin and protect against
renal injury. This hypothesis remains to be tested.
Sex Steroids and Oxidative Stress
Growing evidence links oxidative stress and renal disease,
including drug-induced nephrotoxicity,77,78 IgA nephropathy,79 ischemia-reperfusion injury,80 and diabetic nephropathy.81 Men with these diseases exhibit more renal injury than
women.2 Estradiol is an antioxidant, and ovx increases renal
NADPH oxidase activity and glomerulosclerosis index in
female renal-wrap hypertensive rats; estradiol replacement
abrogated these changes.82 Ovx also worsens adriamycininduced nephropathy and augments oxidative stress, which
Yanes et al
Table.
How Sex Steroids May Modulate Renal Injury
Sex Steroid Effects
Mechanisms
Estradiol
Progesterone
Testosterone/DHT
Renal Ang II
dec
dec?
inc
AT1 receptors
downregulate
?
no effect
ND
?
inc?
Endothelin
Oxidative stress
antioxidant
antioxidant
pro-oxidant
Vascular effect
Acute
vasodilator
vasodilator
vasodilator
Chronic
vasodilator
vasoconstrictor
vasoconstrictor
?
inc
inc
Sodium reabsorption
Sex and Renal Disease
979
nisms by which sex steroids impact CKD in humans will
allow improvement of treatment paradigms that could be
made specific if the patient is male or female. The role played
by sex steroids in renal disease remains an exciting area for
research in humans or animals.
Sources of Funding
J.C. Sartori-Valinotti and L.L. Yanes are recipients of American
Heart Association, Southeast Affiliate, Postdoctoral Fellowships
(#725561B and 0425461B, respectively). This work was supported
by HL51971, HL69194, and HL66072 from the National Institutes of
Health. L.L.Y. has received an AHA grant ⬎$10 000; J.C.S.-V. has
received an AHA grant ⬎$10 000; J.F.R. has received 3 grants
⬎$10 000 each.
Ang II indicates angiotensin II; AT1, angiotensin type 1; dec, decrease; inc,
increase.
Disclosures
None.
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was prevented by estradiol.78 Androgens are thought to
increase oxidative stress. In humans, men have higher levels
of indicators of oxidative stress than age-matched, premenopausal women.83 However, postmenopausal women have
higher levels of oxidative stress than do their premenopausal
counterparts.84 Few studies have examined sex differences in
renal injury and the role of oxidative stress. BP in male SHR
is reduced with antioxidants, such as tempol or apocynin, but
not in females.85 Sullivan and colleagues reported that the
activities of superoxide dismutase and catalase were augmented in kidneys from male SHR compared to females.86
Renal antioxidant enzyme expression is higher in male SHR
than in females.85 However, unlike in male WKY rats, male
SHR fail to upregulate renal expression of antioxidant enzymes when oxidative stress is increased with molsidomine.85
Whether oxidative stress is higher in male or female SHR is
dependent on the tissue and on the age of the animals. In
kidneys, oxidative stress, measured as increases in F2isoprostane or lucigenin chemiluminescence, is slightly lower
or similar in females and males.85 However, we have not
examined whether renal damage in aging male SHR is
ameliorated with chronic antioxidants, although BP is reduced, and therefore renal injury is also likely lessened.
Whether in humans antioxidant therapy can attenuate or
prevent CKD is unclear at the present.
Perspectives
The role that sex steroids play in CKD and in the progression
to ESRD in humans is not clear. Sex steroids may not be
causative of CKD in humans but are likely to be permissive
of or protective against progression to ESRD. The mechanisms by which sex steroids could modulate renal disease are
many, but in the Table , some of the possible mechanisms and
how the sex steroids could affect these mechanisms are
shown. Estradiol is mainly antioxidant, vasodilatory, and Ang
II action-“inhibitory,” although not overtly so. The effect of
estradiol on renal endothelin is not clear. Progesterone has
been less well studied, but it is likely to be vasoconstricting
chronically, antioxidant, antinatriuretic. The effect of progesterone on Ang II, AT1 receptor, and endothelin is not clear.
Androgens, testosterone, and dihydrotestosterone are chronically vasoconstricting, prooxidant, antinatriuretic, and Ang II
and endothelin-action stimulatory. Discovery of the mecha-
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Hypertension. 2008;51:976-981; originally published online February 7, 2008;
doi: 10.1161/HYPERTENSIONAHA.107.105767
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