© 2016 Kitada et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.
php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work
you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For
permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
International Journal of Nephrology and Renovascular Disease 2016:9 279–290
International Journal of Nephrology and Renovascular Disease Dovepress
submit your manuscript | www.dovepress.com
Dovepress
279
REVIEW
open access to scientific and medical research
Open Access Full Text Article
http://dx.doi.org/10.2147/IJNRD.S103784
Rodent models of diabetic nephropathy: their
utility and limitations
Munehiro Kitada
1,2
Yoshio Ogura
2
Daisuke Koya
1,2
1
Division of Anticipatory Molecular
Food Science and Technology, Medical
Research Institute,
2
Department
of Diabetology and Endocrinology,
Kanazawa Medical University,
Uchinada, Ishikawa, Japan
Abstract: Diabetic nephropathy is the most common cause of end-stage renal disease.
Therefore, novel therapies for the suppression of diabetic nephropathy must be developed. Rodent
models are useful for elucidating the pathogenesis of diseases and testing novel therapies, and
many type 1 and type 2 diabetic rodent models have been established for the study of diabetes
and diabetic complications. Streptozotocin (STZ)-induced diabetic animals are widely used as
a model of type 1 diabetes. Akita diabetic mice that have an Ins2+/C96Y mutation and OVE26
mice that overexpress calmodulin in pancreatic β-cells serve as a genetic model of type 1 dia-
betes. In addition, db/db mice, KK-Ay mice, Zucker diabetic fatty rats, Wistar fatty rats, Otsuka
Long-Evans Tokushima Fatty rats and Goto-Kakizaki rats serve as rodent models of type 2
diabetes. An animal model of diabetic nephropathy should exhibit progressive albuminuria and
a decrease in renal function, as well as the characteristic histological changes in the glomeruli
and the tubulointerstitial lesions that are observed in cases of human diabetic nephropathy. A
rodent model that strongly exhibits all these features of human diabetic nephropathy has not
yet been developed. However, the currently available rodent models of diabetes can be useful
in the study of diabetic nephropathy by increasing our understanding of the features of each
diabetic rodent model. Furthermore, the genetic background and strain of each mouse model
result in differences in susceptibility to diabetic nephropathy with albuminuria and the develop-
ment of glomerular and tubulointerstitial lesions. Therefore, the validation of an animal model
reproducing human diabetic nephropathy will significantly facilitate our understanding of the
underlying genetic mechanisms that contribute to the development of diabetic nephropathy. In
this review, we focus on rodent models of diabetes and discuss the utility and limitations of
these models for the study of diabetic nephropathy.
Keywords: diabetic nephropathy, rodent model, albuminuria, mesangial matrix expansion,
tubulointerstitial fibrosis
Introduction
The prevalence of diabetes mellitus has been increasing worldwide in recent years.
Long-term diabetes results in vascular changes and dysfunction, and complications
of diabetes are the major causes of morbidity and mortality in diabetic patients.
Among the vascular complications of diabetes, diabetic nephropathy develops in
40% of patients and remains the leading cause of end-stage renal disease (ESRD)
worldwide.
1
Multifactorial management, including diet therapy and glycemic, blood
pressure (BP), and lipid control, is recommended for diabetic nephropathy.
2
Some
patients with advanced diabetic nephropathy rapidly progress to ESRD, despite
having received adequate multifactorial treatment. Therefore, a novel and more
Correspondence: Munehiro Kitada
Department of Diabetology and
Endocrinology, Kanazawa Medical
University, 1-1 Daigaku, Uchinada,
Ishikawa 9200293, Japan
Email kitta@kanazawa-med.ac.jp
Journal name: International Journal of Nephrology and Renovascular Disease
Article Designation: REVIEW
Year: 2016
Volume: 9
Running head verso: Kitada et al
Running head recto: Features of rodent models of diabetic nephropathy
DOI: http://dx.doi.org/10.2147/IJNRD.S103784
International Journal of Nephrology and Renovascular Disease downloaded from https://www.dovepress.com/ on 26-Aug-2022
For personal use only.
This article was published in the following Dove Press journal:
International Journal of Nephrology and Renovascular Disease
14 November 2016
Number of times this article has been viewed
International Journal of Nephrology and Renovascular Disease 2016:9
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
280
Kitada et al
beneficial treatment to suppress diabetic nephropathy has
to be developed.
In humans, diabetic nephropathy manifests as a clini-
cal syndrome consisting of albuminuria, a progressive
decline in renal function, and an increased risk of devel-
oping cardiovascular disease.
2
Clinically, albuminuria
is the hallmark biomarker for the diagnosis of diabetic
nephropathy, and it is also used to stage diabetic nephropa-
thy. The histopathological features of diabetic nephropathy
in humans include glomerular hypertrophy, a thickening
of the glomerular basement membrane, and mesangial
matrix expansion, including the formation of glomerular
nodular lesions known as Kimmelstiel-Wilson nodules.
3,4
In addition to glomerular lesions, tubulointerstitial lesions
contribute significantly to the decline in renal function in
human diabetic nephropathy.The decline in renal function
is associated with both glomerulosclerosis and tubulointer-
stitial fibrosis. In particular, the degree of tubulointerstitial
fibrosis, rather than the number of glomerular lesions, is
recognized as the most important predictive factor for
progressive renal decline.
5,6
Therefore, an animal model
of diabetic nephropathy should exhibit this characteristic
of renal histology in the glomeruli and tubulointerstitial
area, which is associated with increased albuminuria and
a decline in renal function.
The nephropathy subcommittee of the Animal Models of
Diabetic Complications Consortium (AMDCC) has published
the following validation criteria for rodent models of diabetic
nephropathy based on the clinical and pathological features of
human diabetic nephropathy: 1) >50% decrease in renal func-
tion, 2) >10-fold increase in albuminuria, and 3) pathological
features, including advanced mesangial matrix expansion (±
nodules), thickening of the glomerular basement membrane,
arteriolar hyalinosis, and tubulointerstitial fibrosis.
7
A rodent
model that completely develops all of these features of human
diabetic nephropathy is not currently available. However, the
available rodent models of diabetes can be useful in the study
of diabetic nephropathy by increasing our understanding of
the features of each diabetic rodent model. In this review, we
focus on streptozotocin (STZ)-induced type 1 diabetic and
genetically modified type 1 or type 2 diabetic rodent models,
and we discuss the utility and limitations of these models for
the study of diabetic nephropathy.
Rodent models of type 1 diabetes
STZ-induced type 1 diabetes in mice
STZ, which is toxic to pancreatic β-cells, results in abso-
lute insulin deficiency and is widely used for the induction
of experimental type 1 diabetes in rodents.
8
In addition to
pancreatic β-cells, STZ may also have toxic effects on other
organs, including the kidney.
9
Therefore, the administra-
tion of high doses of STZ (150–200 mg/kg) to mice should
be avoided. To minimize the nonspecific toxicity of STZ,
multiple injections of low doses of STZ have been used to
induce diabetes by causing repetitive low-grade cell damage
accompanied by the lymphocytic infiltration of the pancreatic
islets.
10
This method consists of daily intraperitoneal injec-
tions of 40–50 mg/kg of STZ for 5 consecutive days and
is recommended in the AMDCC protocol. At later stages,
STZ-induced diabetic mice may exhibit significant weight
loss, possibly as a result of the catabolic effects of insulin
deficiency and severe hyperglycemia, as well as the volume
depletion associated with osmotic diuresis. Furthermore,
STZ-induced diabetic mice do not develop hypertension. For
long-term studies, intermittent treatment with small amounts
of insulin that are sufficient to reverse weight loss without
reversing hyperglycemia may be considered.
The STZ-induced mouse model of diabetes is widely
used for numerous studies in the field of diabetes and dia-
betic complications. However, previous reports have shown
that differences in susceptibility to diabetic nephropathy
exist in mice based on the genetic background and strain.
7
Therefore, when the STZ-induced mice model of diabetes
is used to study diabetic nephropathy, we must consider the
genetic background and strain of the mice and the features
of kidney injury, including albuminuria/proteinuria and
histological changes.
C57BL/6
C57BL/6 mice are the most commonly used strain in pre-
clinical research, and many genetic modifications have been
performed on this background because these mice breed well,
have long life spans, and have a low susceptibility to tumors.
7
However, this strain is relatively resistant to the development
of renal injury in experimental models of kidney diseases,
including diabetic nephropathy.
7
C57BL/6 mice with STZ-
induced diabetes exhibit mild to moderate albuminuria at
6 months after the induction of diabetes, but the increase is
less than 10-fold compared to non-diabetic control mice.
11
Qi
et al
12
have also shown that control C57BL/6J mice exhibit a
urinary albumin/creatinine (Cr) ratio of 45.6 ± 12.4 before
vehicle injection, 20.1 ± 1.6 at 5 weeks, 48.11 ± 16.5 at
15 weeks, and 53.2 ± 24.3 μg/mg Cr at 25 weeks after vehicle
injection; in contrast, STZ-induced diabetic C57BL/6J
mice exhibit a higher urinary albumin/Cr ratio of 36.9 ± 7.6
before the induction of diabetes, and the ratios are 35.4 ± 5.7
Powered by TCPDF (www.tcpdf.org)
International Journal of Nephrology and Renovascular Disease 2016:9
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
281
Features of rodent models of diabetic nephropathy
at 5 weeks, 29.5 ± 12.4 at 15 weeks, and 72.1 ± 20.4 μg/mg Cr
at 25 weeks after the induction of diabetes, which were higher
than those of the control C57BL/6J mice.
12
Renal pathological
changes, including glomerular hypertrophy, a thickening of
the glomerular basement membrane, and mild to moderate
mesangial matrix expansion, were observed in STZ-induced
diabetic C57BL/6 mice at more than 6 months after the
induction of diabetes.
11,12
Oxidative stress and inflammation,
which are strongly implicated in the pathogenesis of diabetic
nephropathy, have also been observed in the kidneys of STZ-
induced diabetic C57BL/6 mice.
13,14
However, albuminuria
and renal pathological changes are less commonly observed
in diabetic C57BL/6 mice than in other strains, such as the
DBA/2 and CD1 mice that are described in the later text.
7,11,12
In addition, although renal tubular damage, such as enlarge-
ment of the tubule and tubular cell atrophy, has been observed
in diabetic C57BL/6 mice, tubulointerstitial fibrosis does
not occur.
11
Thus, STZ-induced diabetic C57BL/6 mice may
be useful for elucidating the early pathogenesis of diabetic
nephropathy. However, C57BL/6 mice are usually less sus-
ceptible to STZ-induced, diabetes-associated renal injury
than other strains, such as DBA/2 and CD1 mice.
DBA/2
STZ-induced diabetic DBA/2 mice exhibit albuminuria at
5 weeks after the induction of diabetes and develop more
marked albuminuria after 25 weeks more compared to
C57BL/6 mice.
12
In detail, control DBA/2 mice exhibit uri-
nary albumin/Cr ratios of 19.7 ± 5.1 before vehicle injection,
48.7 ± 7.0 at 5 weeks, 71.1 ± 15.2 at 15 weeks, and 65.8 ±
13.2 μg/mg Cr at 25 weeks after vehicle injection. In contrast,
STZ-induced diabetic DBA/2 mice exhibit higher urinary
albumin/Cr ratios of 26.6 ± 6.6 before the induction of dia-
betes, 424.4 ± 89.4 at 5 weeks, 608.0 ± 220.8 at 15 weeks,
and 421.4 ± 167.3 μg/mg Cr at 25 weeks after induction of
diabetes. Additionally, diabetic DBA/2 mice exhibit some
of the pathological features of human diabetic nephropathy
including nodular glomerulosclerosis, arteriolar hyalinosis,
thickening of the glomerular basement membrane, and
severe mesangial matrix expansion at 25 weeks after the
induction of diabetes. Furthermore, renal tubular damage,
including enlargement of the tubule and tubular cell atrophy,
is observed in STZ-induced diabetic DBA mice. However,
tubulointerstitial fibrosis does not occur.
11
Although diabetic
C57BL/6 mice can live at more than 45 weeks after the onset
of hyperglycemia, the mortality rate of diabetic DBA/2 mice
is markedly increased after 25 weeks of hyperglycemia, with
40% of these mice dying by this time.
12
Thus, STZ-induced
diabetic DBA/2 mice are highly susceptible to renal injury
compared with C57BL/6 mice, and they may be useful as a
model of diabetic nephropathy.
CD1
Sugimoto et al
11,15
have reported that STZ-induced diabetic
CD1 mice develop chronic renal injury associated with tubu-
lointerstitial fibrosis and decreased renal function within 6
months after a single intraperitoneal injection of STZ (200
mg/kg). They also compared the development of renal histol-
ogy and albuminuria in the STZ-induced diabetic CD1 mice
to the development of these conditions in the C57BL/6 and
129/Sv strains. All these mice strains treated with STZ exhib-
ited glomerular lesions, including moderate mesangial matrix
expansion, increased glomerular surface area, and tubular cell
damage. However, nodular lesions in the glomeruli were not
observed. The levels of albuminuria, which were estimated
using the urinary albumin/Cr ratio, were moderately and more
than 10-fold higher in the STZ-induced CD1 mice than in
the control CD1 mice. In contrast, STZ-injected C57BL/6J
and 129/Sv mice exhibited a less than 10-fold increase in the
urinary albumin/Cr ratio compared with the control mice.
11
Tubulointerstitial fibrosis developed in the STZ-induced
diabetic CD1 mice, but not in the C57BL/6 and 129/Sv mice.
Although the reasons why the diabetic CD1 mice exhibited
tubulointerstitial fibrosis are not clear, genetic background
is an important factor in the utility of an animal model for
elucidating the mechanisms of advanced diabetic nephropa-
thy. Therefore, STZ-induced diabetic CD1 mice may be a
useful model for investigating the pathologies associated
with advanced human diabetic nephropathy.
129/Sv
Together with C57BL/6 mice, 129/Sv mice are one of the
most commonly used strains for studying diseases. The 129/
Sv strain develops more significant glomerulosclerosis, pro-
teinuria, increases in BP, and apparent renal failure compared
with C57BL/6 mice after 5/6 nephrectomy.
16
In studies of
hypertension induced with deoxycorticosterone acetate
(DOCA) salt, 129/Sv mice were more susceptible to eleva-
tions in BP, glomerular sclerosis, tubulointerstitial fibrosis,
and albuminuria than C57BL/6 mice.
17
Susceptibility to the
development of hypertension and further glomerulosclerosis
in 129/Sv and C57BL/6 strains may be influenced by renin
gene polymorphisms because some mouse strains, includ-
ing C57BL/6, have one renin gene (Ren-1
c
), whereas other
strains, including 129/Sv, have two renin genes (Ren-1
d
and
Ren-2).
18
Therefore, the accelerated renal injuries, such as
Powered by TCPDF (www.tcpdf.org)
International Journal of Nephrology and Renovascular Disease 2016:9
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
282
Kitada et al
glomerular sclerosis and tubulointerstitial damage after 5/6
nephrectomy or the induction of DOCA salt hypertension,
that are observed in 129/Sv mice may be mediated through
both the hemodynamic and nonhemodynamic effects of
the increased renin levels and the activation of the renin–
angiotensin–aldosterone system. However, no reports have
examined whether this susceptibility to renal injury and
hypertension in 129/Sv contributes to the advanced progres-
sion of diabetic nephropathy compared to C57BL/6 and
other strains of mice. Previous reports have shown that 129/
Sv mice with STZ-induced diabetes exhibit mild to moder-
ate albuminuria, but there is a less than 10-fold increase in
the urinary albumin/Cr ratio compared with control mice.
11
Renal histological changes observed in STZ-induced dia-
betic 129/Sv mice include a mild to moderate increase in
mesangial matrix accumulation and tubular damage, which
were also observed in STZ-induced diabetic C57BL/6 mice.
11
Tubulointerstitial fibrosis was not observed in STZ-induced
diabetic 129/Sv mice, which was also similar to the C57BL/6
and DBA/2 mice with diabetes. Thus, 129/Sv mice exhibit
a lower susceptibility to STZ-induced diabetic renal injury
with histological changes than DBA/2 and CD1 mice.
STZ-induced diabetic rats
STZ-induced diabetic rats have also been used to study
diabetic nephropathy. Diabetes is usually induced in male
Sprague-Dawley (S-D) or other rats weighing 170–200 g
by a single intravenous injection of STZ (50–55 mg/kg
body weight).
19,20
Mima et al
21
demonstrated that urinary
albumin excretion in STZ-induced diabetic S-D rats (12 ±
1.3 mg/day) was higher than in control rats (1.0 ± 0.5 mg/day)
at 24 weeks after the induction of diabetes.
21
Renal func-
tion evaluated by creatinine clearance (Ccr) showed an
increase in diabetic rats (26 ± 9.0 mL/day/100 g body wt)
compared with control rats (8.3 ± 0.2 mL/day/100 g body
wt). The BPs were not significantly different between the
STZ-induced diabetic and control rats, and the STZ-induced
diabetic rats did not develop hypertension. Morphologically,
the diabetic rats exhibited an increase in mesangial matrix
proteins, mesangial matrix fraction, and accumulation of
type 4 collagen compared to the control rats. However, no
severe mesangial matrix accumulation, nodular lesions in
the glomeruli, severe tubular cell damage, or tubulointer-
stitial fibrosis was observed. Additionally, oxidative stress
and inflammation were observed in the kidneys of diabetic
rats.
19,20,22
Thus, STZ-induced diabetic rats may be useful as
a model of early changes in diabetic nephropathy. However,
the hyperglycemia-induced morphological changes in the
kidneys of this rat model were less significant than those
observed in the STZ-induced diabetic mice.
Genetic models of type 1 diabetes
in mice
Akita Ins2+/C96Y mutant mice
Akita mice have Ins2+/C96Y mutation, which is a single
nucleotide substitution in the Ins2 gene.
23
The Ins2+/C96Y
mutation causes abnormal folding of the insulin protein and
toxic injury to pancreatic β-cells, as well as a diminished
capacity to secrete insulin, which results in the develop-
ment of type 1 diabetes. Originally, Akita diabetic mice of
the C57BL/6 strain developed modest levels of albuminuria
and modest structural changes, including an increase in the
mesangial matrix, thickening of glomerular basement mem-
brane, and depletion of podocytes, which were partially due
to increased apoptosis.
24,25
Additionally, many studies have
reported oxidative stress and inflammation in the kidneys of
Akita Ins2+/C96Y C57BL/6 mice, which play an important
role in the pathogenesis of diabetic nephropathy.
26–30
However,
the genetic background of Akita mutation mice contributes to
the severity of albuminuria and histological changes. Gurley
et al
31
studied the effect of breeding the Ins2+/C96Y muta-
tion into the DBA/2 and 129/SvEv strains on susceptibility
to diabetic nephropathy.
31
They found that C57BL/6, DBA/2,
and 129/SvEv mice with the Akita mutation developed
similar degrees of hyperglycemia, but they differed in their
manifestations of diabetes-induced renal injury. The DBA/2-
Ins2+/C96Y mice exhibited more albuminuria (345 ± 110 μg/
day) than the other strains (129/SvEv-Ins2+/C96Y: 151 ± 77
μg/day; C57BL/6-Ins2+/C96Y: 40 ± 3 μg/day), but only the
C57BL/6 and 129/SvEv mice exhibited a moderate increase
in mesangial matrix accumulation at 6 months of age.
31
Significant strain differences in baseline BPs also existed in
the nondiabetic controls. Systolic BPs were higher in both
the nondiabetic 129/SvEv-Ins2+/+ (130 ± 4 mmHg) and
DBA/2-Ins2+/+ animals (134 ± 2 mmHg) compared with
the C57BL/6-Ins2+/+ group (103 ± 2 mmHg). The effects of
diabetes on BP also varied among the strains. Systolic BPs
were significantly higher in the C57BL/6-Ins2+/C96Y (112 ±
4 vs. 103 ± 2 mmHg) and 129/SvEv-Ins2+/C96Y groups
(143 ± 3 vs. 130 ± 4 mmHg) compared to their respective
Ins2+/+ wild-type mice. In contrast, there were no differ-
ences in BP between the 6-month-old DBA/2-Ins2+/C96Y
mice and the DBA/2-Ins2+/+ wild-type controls (134 ± 3 vs.
134 ± 2 mmHg).
31
Regardless of the strain, the Akita mice
exhibited none of the structural alterations that are observed
Powered by TCPDF (www.tcpdf.org)
International Journal of Nephrology and Renovascular Disease 2016:9
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
283
Features of rodent models of diabetic nephropathy
in advanced human diabetic nephropathy, such as mesangiol-
ysis, widespread marked or nodular mesangial sclerosis, and
tubulointerstitial fibrosis. Thus, Akita Ins2+/C96Y mutation
mice may be a useful model of early to moderately advanced
renal morphological changes in diabetic nephropathy. How-
ever, the susceptibility to diabetic nephropathy is dependent
on the strain of the mouse.
Furthermore, Haseyama et al
32
reported that Akita mice
with a C57BL/6 genetic background develop diffuse granular
mesangial deposits of immunoglobulin A (IgA) starting at 20
weeks of age.
32
Compared to controls, male Akita diabetic
mice, but not female mice, develop impaired renal func-
tion with an elevation of serum IgA after 30 weeks of age.
However, Akita mice with other genetic backgrounds have
not been evaluated for mesangial depositions of IgA. The
mesangial deposition of IgA is a major cause of mesangial
proliferative glomerulonephritis. Therefore, using Akita
mice of the C57BL/6 strain may be problematic and may
limit the evaluation of diabetic nephropathy-induced altera-
tions in mesangial area and mesangial matrix accumulation.
Therefore, Akita mice are a unique mouse model that exhibits
diabetes-related glomerular lesions, including mesangial
sclerosis, and possibly IgA nephropathy.
OVE26 FVB mice
OVE26 mice are characterized by the transgenic overexpres-
sion of calmodulin in pancreatic β-cells, which results in
the development of type 1 diabetes due to deficient insulin
production within the first week of life.
33
Male heterozygous
OVE26 diabetic mice are bred with female wild-type FVB
mice, and the resulting OVE26 mice exhibit significant albu-
minuria by 2 months of age. Albuminuria increases progres-
sively with age and is markedly increased at 9 months of age
(average urinary albumin excretion exceeding 15 mg/24 hr).
The glomerular filtration rate (GFR) of OVE26 mice sig-
nificantly increases from 2 to 3 months of age and then
decreases significantly from 5 to 9 months, and the GFR of
9-month-old diabetic mice is significantly lower than that of
9-month-old control mice. Diastolic BP, as measured with a
tail cuff, has been shown to be elevated in conscious OVE26
mice at 3 months of age compared to non-diabetic mice. By
8 months of age, OVE26 mice exhibit significant elevations
in both diastolic and systolic BP compared to non-diabetic
mice (approximately 130/90 mmHg vs. 120/80 mmHg).
The kidney weights of OVE26 mice show an almost twofold
increase between 2 and 5 months. Diabetic OVE26 mice
also exhibit progressively enlarged glomeruli, a thickening
of the glomerular basement membrane, podocyte loss, and a
marked increase in mesangial area with diffuse and nodular
expansion of the mesangial matrix.
34
Additionally, tubuloin-
terstitial fibrosis has been observed in diabetic OVE26 mice.
Diabetes-induced oxidative stress and inflammation in the
kidneys of OVE26 mice have also been observed and are
related to the pathogenesis of diabetic nephropathy.
30
OVE26
mice exhibit most of the characteristics of advanced human
diabetic nephropathy with chronic hyperglycemia. There-
fore, this mouse model may increase our understanding of
the pathophysiology of diabetes and lead to treatments for
diabetic nephropathy. However, difficulties with the viability
of these mice have been reported.
35
Rodent models of type 2 diabetes
Mouse model
db/db mice
db/db mice are the most widely used model of type 2 dia-
betes.
36
They have a deletion mutation in the leptin receptor
(LepRdb/db) that results in abnormal splicing and a defective
receptor for the adipocyte-derived hormone leptin.
37
The
defect in leptin signaling produced by the LepRdb/db deletion
affects hypothalamic responses, leading to the development
of hyperphagia, obesity, hyperlipidemia, hyperinsulinemia,
insulin resistance, and diabetes. Diabetes is more severe in
male mice than in female mice. The LepRdb/db mutation
was originally recognized in the C57BLKS/J strain and was
modified to contain part of the DBA/2 strain,
38
which exhibits
several features of human diabetic nephropathy, because the
identical mutation in mice of the C57BL/6 strain does not
result in significant diabetic nephropathy. Male C57BLKS/J
db/db mice rapidly develop hyperglycemia at 6–10 weeks of
age and moderate to severe albuminuria at 8–25 weeks of
age. Moderate to marked albuminuria at 8–25 weeks ranges
from 68 to 600 μg/24 hr in the db/db male mouse model,
39–46
whereas it is between 4 and 44 μg/24 hr in age-matched, het-
erozygous littermates, non -diabetic db/m (m+/+ LepRdb).
7
The degree of albuminuria does not consistently increase with
the duration of diabetes, as similar levels of albuminuria have
been observed between 8 and 25 weeks.
38,43
Renal function in
these diabetic mice declines at 15–18 weeks, and their islet
cells are sensitive to the toxic effects of hyperglycemia. These
mice eventually become dependent on insulin administration
to control their increasing blood glucose levels and survive.
db/db mice at 17 weeks of age show no obvious hypertension,
but the mean blood pressures of db/db mice (102.8 ± 6.56
mmHg) are significantly higher than those of db/m mice (94.7
± 5.3 mmHg).
44
db/db mice of the C57BLKS/J strain develop
Powered by TCPDF (www.tcpdf.org)