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Aromatase deficiency causes altered expression of molecules critical for calcium reabsorption in the kidneys of female mice *.
[aromatase deficiency]
Kidney
stones
increase
after
menopause
,
suggesting
a
role
for
estrogen
deficiency
.
ArKO
mice
have
hypercalciuria
and
lower
levels
of
calcium
transport
proteins
,
whereas
levels
of
the
klotho
protein
are
elevated
.
Thus
,
estrogen
deficiency
is
sufficient
to
cause
altered
renal
calcium
handling
.
The
incidence
of
renal
stones
increases
in
women
after
menopause
,
implicating
a
possible
role
for
estrogen
deficiency
.
We
used
the
aromatase
deficient
(
ArKO
)
mouse
,
a
model
of
estrogen
deficiency
,
to
test
the
hypothesis
that
estrogen
deficiency
would
increase
urinary
calcium
excretion
and
alter
the
expression
of
molecular
regulators
of
renal
calcium
reabsorption
.
Adult
female
wildtype
(
WT
)
,
ArKO
,
and
estradiol-treated
ArKO
mice
(
n
=
5
-
12
/
group
)
were
used
to
measure
urinary
calcium
in
the
fed
and
fasting
states
,
relative
expression
level
of
some
genes
involved
in
calcium
reabsorption
in
the
distal
convoluted
tubule
by
real-time
PCR
,
and
protein
expression
by
Western
blotting
or
immunohistochemistry
.
Plasma
membrane
calcium
ATPase
(
PMCA
)
activity
was
measured
in
kidney
membrane
preparations
.
ANOVA
was
used
to
test
for
differences
between
groups
followed
by
posthoc
analysis
with
Dunnett
's
test
.
Compared
with
WT
,
urinary
Ca
:
Cr
ratios
were
elevated
in
ArKO
mice
,
renal
mRNA
levels
of
transient
receptor
potential
cation
channel
vallinoid
subfamily
member
5
(
TRPV
5
)
,
TRPV
6
,
calbindin-
D
28
k
,
the
Na
+
/
Ca
+
exchanger
(
NCX
1
)
,
and
the
PMCA
1
b
were
significantly
decreased
,
and
klotho
mRNA
and
protein
levels
were
elevated
.
Estradiol
treatment
of
ArKO
mice
normalized
urinary
calcium
excretion
,
renal
mRNA
levels
of
TRPV
5
,
calbindin-
D
(
28
k
)
,
PMCA
1
b
,
and
klotho
,
as
well
as
protein
levels
of
calbindin-
D
28
k
and
Klotho
.
ArKO
mice
treated
with
estradiol
had
significantly
greater
PMCA
activity
than
either
untreated
ArKO
mice
or
WT
mice
.
Estrogen
deficiency
caused
by
aromatase
inactivation
is
sufficient
for
renal
calcium
loss
.
Changes
in
estradiol
levels
are
associated
with
coordinated
changes
in
expression
of
many
proteins
involved
in
distal
tubule
calcium
reabsorption
.
Estradiol
seems
to
act
at
the
genomic
level
by
increasing
or
decreasing
(
klotho
)
protein
expression
and
nongenomically
by
increasing
PMCA
activity
.
PMCA
,
not
NCX
1
,
is
likely
responsible
for
extruding
calcium
in
response
to
in
vivo
estradiol
hormonal
challenge
.
These
data
provide
potential
mechanisms
for
regulation
of
renal
calcium
handling
in
response
to
changes
in
serum
estrogen
levels
.
Diseases
Validation
Diseases presenting
"coordinated changes in expression of many proteins involved in distal tubule calcium reabsorption"
symptom
aromatase deficiency
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