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Hydroxyproline metabolism in mouse models of primary hyperoxaluria.
[primary hyperoxaluria type 1]
Primary
hyperoxaluria
type
1
(
PH
1
)
and
type
2
(
PH
2
)
are
rare
genetic
diseases
that
result
from
deficiencies
in
glyoxylate
metabolism
.
The
increased
oxalate
synthesis
that
occurs
can
lead
to
kidney
stone
formation
,
deposition
of
calcium
oxalate
in
the
kidney
and
other
tissues
,
and
renal
failure
.
Hydroxyproline
(
Hyp
)
catabolism
,
which
occurs
mainly
in
the
liver
and
kidney
,
is
a
prominent
source
of
glyoxylate
and
could
account
for
a
significant
portion
of
the
oxalate
produced
in
PH
.
To
determine
the
sensitivity
of
mouse
models
of
PH
1
and
PH
2
to
Hyp-derived
oxalate
,
animals
were
fed
diets
containing
1
%
Hyp
.
Urinary
excretions
of
glycolate
and
oxalate
were
used
to
monitor
Hyp
catabolism
and
the
kidneys
were
examined
to
assess
pathological
changes
.
Both
strains
of
knockout
(
KO
)
mice
excreted
more
oxalate
than
wild-
type
(
WT
)
animals
with
Hyp
feeding
.
After
4
wk
of
Hyp
feeding
,
all
mice
deficient
in
glyoxylate
reductase
/
hydroxypyruvate
reductase
(
GRHPR
KO
)
developed
severe
nephrocalcinosis
in
contrast
to
animals
deficient
in
alanine-glyoxylate
aminotransferase
(
AGXT
KO
)
where
nephrocalcinosis
was
milder
and
with
a
lower
frequency
.
Plasma
cystatin
C
measurements
over
4
-
wk
Hyp
feeding
indicated
no
significant
loss
of
renal
function
in
WT
and
AGXT
KO
animals
,
and
significant
and
severe
loss
of
renal
function
in
GRHPR
KO
animals
after
2
and
4
wk
,
respectively
.
These
data
suggest
that
GRHPR
activity
may
be
vital
in
the
kidney
for
limiting
the
conversion
of
Hyp-derived
glyoxylate
to
oxalate
.
As
Hyp
catabolism
may
make
a
major
contribution
to
the
oxalate
produced
in
PH
patients
,
Hyp
feeding
in
these
mouse
models
should
be
useful
in
understanding
the
mechanisms
associated
with
calcium
oxalate
deposition
in
the
kidney
.
