Am J Physiol Renal Physiol 284: F1138–F1144, 2003;
10.1152/ajprenal.00315.2002.
invited review
Diabetic kidney disease in the db/db mouse
Kumar Sharma,1 Peter McCue,2 and Stephen R. Dunn1
1
Dorrance Hamilton Research Laboratory, Division of Nephrology, Department of Medicine, and 2Department
of Anatomy, Cell Biology and Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
diabetic nephropathy; creatinine; albuminuria; mesangial matrix
was identified initially in 1966 in Jackson Labs as an obese mouse that was hyperphagic soon
on weaning (13). The diabetic gene (db) is transmitted
as an autosomal recessive trait. The db gene encodes
for a G-to-T point mutation of the leptin receptor,
leading to abnormal splicing and defective signaling of
the adipocyte-derived hormone leptin (1, 15). Lack of
leptin signaling in the hypothalamus will lead to persistent hyperphagia and obesity with consequently
high leptin and insulin levels. The recognition of diabetes initially was recognized in mice from the
C57BLKS/J strain. The C57BLKS/J mouse shares 84%
of its alleles with the common C57BL/6 strain and 16%
with the DBA/2J strain and was initially maintained
by Dr. N. Kaliss (KS). The updated nomenclature from
Jackson Labs uses the term C57BLKS/JLepr (KS for
Kaliss) to designate the db/db mouse in the C57 black
Kaliss background (Jackson Labs, http://jaxmice.jax.
org/jaxmicedb/html/model_66.shtml). For the purpose
of this review, the common name db/db will be used.
The natural history of diabetes and the renal manifestations in the db/db mice have been described primarily in the C57BLKS/J strain. In the C57BL/6J
background, less hyperglycemia is found despite similar degrees of hyperphagia and weight gain (12). This
may be attributed to the development of pancreatic
islet cell hypertrophy in the C57BL/6J background
rather than islet cell degeneration, as seen in the
THE db/db MOUSE
Address for reprint requests and other correspondence: K.
Sharma, Division of Nephrology, Dept. of Medicine, 353 Jeff Alumni
Hall, 1020 Locust St., Philadelphia, PA 19107 (E-mail: kumar.
sharma@mail.tju.edu).
F1138
C57BLKS/J background (12). Another obese, diabetic
mouse is the ob/ob mouse. This ob/ob mouse differs
from the db/db mouse in that it has a deficiency in the
production of leptin but intact leptin signaling. Similar
to the db/db mouse, the ob/ob mouse in the C57BLKS/J
background develops ␤-cell atrophy and severe hyperglycemia, whereas ob/ob mice in the C57BL/6J background develop hyperplasia of the pancreatic ducts and
only mild hyperglycemia (12). Interestingly, the
C57BLKS/J mouse is more susceptible to the effects of
the ␤-cell toxin streptozotocin compared with the
C57BL/6J strain (20). Thus severe susceptibility to
diabetes appears to be present in the KS background
and may be independent of the underlying trigger for
islet dysfunction. The renal disease in ob/ob mice primarily consists of diffuse and nodular lipohyaline
changes in glomeruli (34). The relative paucity of diabetic renal lesions in the ob/ob mouse, compared with
the db/db mouse, may be due to lack of circulating
leptin, as leptin has been found to directly stimulate
matrix production (10); however, part of the difference
may be due to the different backgrounds of the mice
that have been studied.
In the C57BLKS/J db/db mouse, hyperinsulinemia is
noted by 10 days of age and blood glucose levels are
slightly elevated at 1 mo of age (7.2 ⫾ 2.3 mM) (17).
After 1 mo of age, the db/db mice are distinguished
from wild-type and heterozygous mice by the presence
of increased fat deposition in the inguinal and axillary
regions. The db/db mouse develops frank hyperglycemia with glucose values of 9.7 ⫾ 1.6 mM by 8 wk of age
and 15.7 ⫾ 4.3 mM at 10 wk of age (17). There is a
progressive increase in food and water intake associ-
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Sharma, Kumar, Peter McCue, and Stephen R. Dunn. Diabetic
kidney disease in the db/db mouse. Am J Physiol Renal Physiol 284:
F1138–F1144, 2003; 10.1152/ajprenal.00315.2002.—Diabetic nephropathy is increasing in incidence and is now the number one cause of
end-stage renal disease in the industrialized world. To gain insight into
the genetic susceptibility and pathophysiology of diabetic nephropathy,
an appropriate mouse model of diabetic nephropathy would be critical. A
large number of mouse models of diabetes have been identified and their
kidney disease characterized to various degrees. Perhaps the best characterized and most intensively investigated model is the db/db mouse.
Because this model appears to exhibit the most consistent and robust
increase in albuminuria and mesangial matrix expansion, it has been
used as a model of progressive diabetic renal disease. In this review, we
present the findings from various studies on the renal pathology of the
db/db mouse model of diabetes in the context of human diabetic nephropathy. Furthermore, we discuss shortfalls of assessing functional renal
disease in mouse models of diabetic kidney disease.
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INVITED REVIEW
increase (Table 1). Although the absolute values of the
glomerular surface area were over twofold greater in
perfused kidneys (14), compared with nonperfused kidneys (4), the degree of glomerular hypertrophy in the
db/db group was similar (22 and 27% in both studies).
Glomerular hypertrophy at the onset of diabetes may
be due to alteration of glomerular hemodynamics as
there is evidence of glomerular hyperfiltration in db/db
mice during the early stages of diabetes (8). However,
there have not been any studies of glomerular capillary
pressures in db/db mice and the contribution of capillary loop enlargement and cell hypertrophy of the different glomerular cell compartments has not been evaluated.
GLOMERULAR PATHOLOGY
RENAL HYPERTROPHY
At the tissue level, several studies measured renal
size in the db/db mouse. An important caveat is because a large amount of fat envelops the kidneys, to
ensure accurate weight, careful removal of fat tissue is
required before weighing of the kidneys. Table 1 lists
the results of various kidney parameters that have
been reported from several published studies. Evidence of kidney hypertrophy has been noted in db/db
mice at the age of 16 wk (6, 11, 35). Surprisingly, the
kidney weights in the diabetic mice do not remain
significantly increased above control values between
the ages of 21 and 25 wk (Table 1) (14). In 22-wk-old
male mice, we found that the right kidney is significantly heavier than the left kidney in the db/db mice
(right 248 ⫾ 6 vs. left 208 ⫾ 7 mg, P ⬍ 0.05; Sharma
and Dunn, unpublished observations). On the basis of
the above, renal hypertrophy should be evaluated before 16–20 wk of age and both kidneys should be
weighed individually.
GLOMERULAR HYPERTROPHY
Glomerular surface area has been measured using
standard measurements of glomerular tuft areas using
a digital planimeter at various ages of the db/db and
db/m mice (Table 1). Cohen et al. (4) found that glomerular surface area in nonperfused kidneys was increased by 23% at 8 wk of age and remained increased
by 27% at 16 wk of age. Koya et al. (14) studied
glomerular surface area in perfused db/db mouse kidneys at 25 wk of age and also found a significant
An in-depth characterization of renal pathology in
the db/db mouse was first described by Like and colleagues (21) in 1972. In this initial study, mice were
studied at various time intervals, with some mice having their food restricted between weeks 7 and 11 to
allow the mice to live to 12–22 mo of age. Gross examination did not reveal any differences in the kidney,
although calyceal dilation and flattening of the papilla
were notable in diabetic mice older than 5–6 mo of age.
Before the onset of sustained hyperglycemia (4–6 wk of
age), the glomeruli of mice were not distinguishable
from their nondiabetic littermates. By 5–6 mo of age,
diabetic mice had larger glomeruli with increased mesangial matrix by periodic acid-Schiff (PAS) staining.
By 18–20 mo of age, the mesangial matrix and glomerular enlargement became more pronounced and thickening of the glomerular basement membrane (GBM)
was notable. Nodular lesions of the subepithelia basal
lamina were also noted, which were PAS positive. It
should be noted that the described subepithelial nodules were distinct from the Kimmelstein-Wilson nodules described in human diabetic nephropathy. By electron microscopy (EM), the finding of increased mesangial matrix with frequent foci of vacuolar change and
embedded collagen fibrils was found to distinguish
older diabetic mice (5–6 mo of age) from nondiabetic
littermates. GBM thickening and subepithelial nodularity were noted primarily in diabetic mice older than
12 mo of age. In the oldest diabetic mice studied (16–22
mo of age), strikingly large subepithelial nodular densities were observed along with foot process fusion.
Table 1. Renal parameters in C57BLKS/JLepr (db/db and db/m) mice at various ages
db/db
Age 8 wk
Age 12 wk
Age 16 wk
Age 21–25 wk
200 ⫾ 6*
194 ⫾ 6*
260 ⫾ 30
db/m
Ref. no.
130 ⫾ 2
127 ⫾ 2
230 ⫾ 30
Mesangial Matrix Area,
%glomerular area
Glomerular Surface Area, ␮m2
Kidney Weight, mg
11
35
14
db/db
db/m
Ref. no.
1,995 ⫾ 100*
2,325 ⫾ 135*
1,625 ⫾ 115
1,700 ⫾ 190
4
4
2,425 ⫾ 145*
1,915 ⫾ 130
4
5,500 ⫾ 223*
4,250 ⫾ 88
14
db/db
db/m
Ref. no.
4.8 ⫾ 0.2
10.5 ⫾ 0.1*
16.5 ⫾ 0.3*
14.8 ⫾ 0.9*
16.1 ⫾ 2.3
16.6 ⫾ 3.3*
4.0 ⫾ 0.1
4.2 ⫾ 0.1
4.5 ⫾ 0.2
6.7 ⫾ 0.1
9.0 ⫾ 0.64
5.2 ⫾ 0.4
4
4
4
35
17
14
Values are means ⫾ SE. Kidney weights of the right kidney are shown. * P ⬍ 0.05 vs. corresponding value for control group.
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ated with progressive weight gain until 4–5 mo of age.
Food intake averages ⬃40 g/wk between the ages of 4
and 16 wk of age. Water intake averages ⬃30 ml/wk
before the onset of hyperglycemia and increases to 100
ml/wk with worsening hyperglycemia (17). Progressive
hyperglycemia is noted with mean levels of glucose of
28.6 ⫾ 13.2 mM and peak levels reaching as high as 44
mM at 16 wk of age (17, 19). After 5–6 mo of age, the
body weight and insulin levels begin to fall in association with pancreatic islet cell degeneration (12). By this
time, the mice become so obese that they have difficulty
ambulating in the cage and obtaining food and water.
The cause of death is not clear, although ketonuria,
hematuria, and gastrointestinal bleeding have all been
noted during the terminal stage (13).
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INVITED REVIEW
Subsequent studies of diabetic renal pathology were
performed in the early 1980s by Lee and colleagues
(16–19). By morphometric analysis of glomeruli, mesangial matrix enlargement was consistently noted after the age of 16 wk in the db/db mouse. When db/db
mice were placed on caloric restriction by limiting their
time of feeding to 3 h/day, their body weight and the
blood glucose levels were only slightly higher than the
heterozygous control (db/m) mice, and renal pathology
was prevented (17).
A reappraisal of renal pathology in db/db mice by
several groups in the past decade has brought renewed
recognition of this mouse model as a useful tool for the
study of diabetic nephropathy.
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MESANGIAL MATRIX EXPANSION
Diffuse expansion of the mesangial matrix is considered to be the hallmark pathological feature of established diabetic nephropathy in humans (24, 25, 29, 32).
Of the many mouse models of diabetes that have been
identified, the db/db mouse appears to most closely
mimic the progressive nature of mesangial matrix expansion seen in human diabetic nephropathy. The time
course of mesangial matrix expansion was described
recently by Cohen et al. (4) (Table 1). At 8 wk of age,
before the onset of severe hyperglycemia, there is no
discernible increase in the mesangial compartment of
the db/db mouse. At 12 wk of age and after 4–6 wk of
hyperglycemia, a twofold increase in mesangial matrix
was noted. After 16 wk of age, a consistent threefold
increase in mesangial matrix expansion was reported
by several independent studies (4, 6, 14, 35) (Table 1).
Although many of the prior studies were performed
without perfusion of the mouse kidneys, the study by
Koya et al. (14) showed a similar increase in mesangial
matrix expansion in perfused kidneys from db/db mice
of 25 wk of age.
Selected images of PAS-stained glomeruli from db/m
and db/db male mice of 21 wk of age are presented in
Fig. 1. In the normal heterozygous mouse (C57BLKS/J
db/m), the outer cortical glomerulus is of normal size
and configuration (Fig. 1A). Bowman’s capsule is of the
usual caliber, and there is no epithelial cell proliferation. The capillary tuft is fully expanded with patent
capillary loops, and the GBMs appear thin and delicate. The mesangium contains the usual complement
of cells and matrix without matrix expansion, inflammation, or sclerosis. In distinction, the most severely
affected glomerulus from a db/db mouse kidney shown
appears dramatically different (Fig. 1B). The visceral
epithelial cells are swollen and appear prominent. The
glomerular capillary basement membranes appear
thickened, and the peripheral capillary loop appears
collapsed. The mesangium is diffusely and markedly
expanded with PAS-positive matrix material. The
overall cellularity is normal without inflammation or
necrosis. Approximately 30% of glomeruli have a similar appearance, and the remaining have a lesser degree of mesangial matrix expansion. Thus, by light
microscopy, the appearance is very similar to moderate
AJP-Renal Physiol • VOL
Fig. 1. Light microscopic appearance of glomeruli from male nondiabetic control (db/m) mice (A) and diabetic (db/db) mice (B and C) at
21 wk of age. There is diffuse mesangial matrix expansion (B) and
evidence of arteriolar hyalinosis (C) in db/db mice. Renal tissue was
fixed with 10% neutral buffered formalin, and 4-␮m sections were
stained with periodic acid-Schiff. Images are taken at ⫻400
magnification.
human diabetic nephropathy at the glomerular level.
However, there was no evidence of Kimmelstein-Wilson lesions and capsular drop lesions were only rarely
seen. By EM analysis, segmental GBM thickening has
been reported by several studies (11, 21, 22). However,
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INVITED REVIEW
IMMUNOFLUORESCENT STUDIES
Several studies observed diffuse uptake of IgG, IgA,
IgM, and complement in glomeruli of db/db mice at as
early as 8 wk of age (16–19). On the basis of the
study by Like et al. (21) with older db/db mice (⬎8 mo
of age), the presence of subepithelial nodular deposits
under EM may represent immune complexes. However, such lesions have not been described on EM
analysis in the db/db mouse at 16 wk of age (11). It
should also be noted that nondiseased mice from various backgrounds may exhibit glomerular binding of
immunoglobulins, including IgG, IgM, and IgA (23).
The degree of immune complex deposition can be reduced if they are raised in germ-free environments
(23). Therefore, the increased glomerular immunglobulin uptake in the db/db mice may be secondary to
increased susceptibility to infections and resulting immune complex formation. To help clarify the role of
immune complex deposition in relation to the renal
disease of db/db mice, immunofluorescent studies in
db/db mice raised in germ-free environments will be
necessary.
VASCULAR AND TUBULOINTERSTITIUM
Advanced human diabetic nephropathy often exhibits arteriolar hyalinosis and tubular atrophy coupled
with an increase in the interstitial volume (28). These
features are largely absent in the db/db mouse kidney
at 16 wk of age. At the more advanced age (21 wk),
lesions suggestive of arteriolar hyalinosis (Fig. 1C)
were noted. However, it has not been characterized
whether both afferent and efferent arterioles are similarly affected. The tubular changes noted in the db/db
mouse kidney primarily consist of vacuolization of tubular cells (Fig. 1, B and C). No evidence of tubular
atrophy, tubulointerstitial fibrosis, or alterations of the
medullary structure by light microscopy was discernAJP-Renal Physiol • VOL
able. An overall increase in renal collagen content has
been reported in db/db mice (22); however, comprehensive and sensitive studies of tubular and vascular damage have not yet been published.
RENAL FUNCTIONAL MEASUREMENTS
(CLEARANCE STUDIES)
Given that the db/db mouse exhibits a progressive
increase in mesangial matrix expansion in the setting
of severe hyperglycemia, it has been considered an
appropriate model of progressive human diabetic nephropathy. As human diabetic nephropathy is initially
characterized by a supernormal glomerular filtration
rate (GFR) in the early stages and a decline in GFR in
the later stages, measurements of GFR have also been
assessed in db/db mice. GFR was repeatedly measured
in conscious C57BL/6J db/db female mice and
C57BLKS/J mice between 7 and 24 wk of age using
single injections of 51chromium-EDTA (8). As the GFR
values were similar in both strains of db/db mice, the
data were pooled (8). GFR was found to be elevated in
db/db mice as early as 7 wk of age, even though blood
glucose levels were only mildly increased. Between 7
and 14 wk of age, the GFR was ⬃300 ␮l䡠min⫺1 䡠mouse⫺1
in the control mice, whereas the GFR was ⬃700
␮l 䡠 min⫺1 䡠 mouse⫺1 in the db/db mice. After 17 wk of
age, the GFR remained constant in the nondiabetic
mice; however, a marked variability in the GFR was
observed in the db/db mice, with some mice having
GFRs below normal. This study concluded that female
db/db mice do hyperfilter at the onset of hyperglycemia
and that GFR declines with the duration of diabetes.
However, the GFR did not progressively increase in
association with the severity of hyperglycemia and was
similar in both the BL6 and KSJBL6 mice strains.
Recent studies used endogenous creatinine clearance
in the db/db mouse model (4, 35) as an index of renal
function. At 8 wk of age, a twofold increase in creatinine clearance in db/db male mice was observed (4). By
16 wk of age, the creatinine clearance was reduced by
30–50% compared with age-matched control heterozygous mice (4, 35). Blood levels of creatinine correspondingly increased by twofold in db/db mice at 16 wk of age
(4, 35). Thus it appears that the pattern of creatinine
clearance associated with the duration of diabetes in
the db/db mouse corresponds well to actual GFR levels
as reported by Gartner (8). However, by absolute values the calculated creatinine clearance in normal heterozygous mice was on the order of 60 ␮l䡠min⫺1 䡠mouse⫺1
(4), whereas the GFR was ⬃300 ␮l䡠min⫺1 䡠mouse⫺1 by
the 51chromium-EDTA method (8).
The measurement of plasma or serum creatinine is
quite problematic in mice (26, 27). Measurement of
creatinine levels in normal mouse blood by Jaffé alkaline picrate reaction has yielded values ranging from
17 to 106 ␮mol/l (0.2 to 1.2 mg/dl). However, the Jaffé
reaction has been reported to grossly overestimate the
actual plasma creatinine concentration (26, 27). The
actual result based on an assay using HPLC provides
values that are roughly one-third to one-fifth of the
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formal quantitative studies have not been published to
establish the degree of GBM thickening.
The constituents of the mesangial matrix expansion
in the db/db mouse kidney consist of increased type IV
collagen, fibronectin, and laminin (6, 9, 14, 30, 35). By
Northern blot analysis of renal cortex, a two- to eightfold increase in type IV collagen [␣1(IV)] gene expression and a fourfold increase in fibronectin gene expression appeared at 16 wk of age (6, 30, 35). By immunostaining, a marked increase in fibronectin and type IV
collagen was described in glomeruli of db/db mice at 25
wk of age (14). Laminin isoforms-␤1 and -␣5 were
found to be increased in glomeruli of db/db mice by
immunostaining; however, the mRNA levels were decreased in the renal cortex at the same time points (9).
In human diabetic nephropathy, the increase in mesangial matrix expansion has also been associated with
an increase in fibronectin, ␣1(IV) and ␣2(IV) collagen
chains, and laminins (28). Thus a very similar pattern
of the components of mesangial matrix that account for
the expansion in human diabetic nephropathy has
been noted in the db/db mouse.
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INVITED REVIEW
(Sharma and Dunn, unpublished observations). In addition, in unpublished studies, we found that addition
of a high-salt (5%) and high-protein (30%) diet led to a
50% increase in 24-h urinary albumin excretion in
db/db males.
It is of interest that the increase in urinary albumin
excretion has been noted at 8 wk of age (Table 2),
before the development of obvious structural evidence
of alterations of the GBM or the podocytes. By EM
examination, a mild segmental increase in GBM thickening and rare podocyte foot process fusion has been
noted at 16 wk of age (11) (Sharma and Dunn, unpublished observations). Measurement of podocyte numbers as well as podocyte-specific proteins in relation to
the development of albuminuria in the db/db mouse
would be very informative.
BLOOD PRESSURE
In the study by Koya et al. (14), blood pressure was
measured by the tail cuff method at the age of 16 wk in
male db/m and db/db mice. At this time point, the
mean blood pressure was 117 mmHg in db/m mice and
110 mmHg in db/db mice and not significantly different. To our knowledge, no other studies reported blood
pressure measurements in the C57BLKS/J db/db mice.
ALBUMINURIA
With the availability of sensitive and specific
ELISAs for measuring mouse albumin (6), levels of
urinary albumin may easily be followed from mice
placed in metabolic or diuresis cages. Several studies
established that albumin excretion rates are higher by
8- to 62-fold in db/db mice beginning at the age of 8 wk
(Table 2). The range of albuminuria is between 68 and
303 ␮g/24 h in the db/db male mouse, whereas it is
between 4 and 21 ␮g/24 h in the age-matched heterozygous littermate (4, 14). The degree of albuminuria does
not consistently increase with the duration of diabetes
as there are similar levels of albuminuria at 8, 16, 21,
and 25 wk (4, 9, 14, 35).
Interestingly, when urinary protein was measured
by a total protein assay such as the Bradford reaction,
no statistical increase in urinary protein was found in
the 20-wk-old db/db mouse (30). This would suggest
that there is a selective increase in albuminuria in the
db/db mouse and thus can only be detected by an assay
specific for albumin. Although a head-to-head study
has not been performed between db/db females and
db/db males, the db/db males generally have twice
as much albuminuria compared with females (21)
INSIGHTS FROM RECENT INTERVENTIONAL STUDIES
On the basis of the recognition that the db/db mouse
has many similar features of human diabetic nephropathy, several studies were performed in this model to
investigate the role of various candidate pathways in
the progression of diabetic renal disease. Studies by
Cohen et al. (3, 6) found that db/db mice have elevated
glycated albumin and that antibodies against glycated
albumin attenuate albuminuria, mesangial matrix accumulation, and decline in renal function when given
over a course of 8 wk. In addition, an oral inhibitor of
Amadori glucose adducts maintained levels of glycated
albumin in the normal range and exerted beneficial
effects on features of diabetic nephropathy in the db/db
mice (5). The role of PKC-␤ in progressive diabetic
kidney disease has also been assessed in this model.
Glomeruli from db/db mice at 25 wk of age were found
to have a twofold increase in PKC activity (14). In
db/db mice given an oral PKC-␤ inhibitor from week 9
until week 25, normalization of glomerular PKC activity and significant reduction in albuminuria and mesangial matrix expansion were observed (14).
Table 2. Albuminuria in C57BLKS/JLepr (db/db and db/m) mice at various ages
Albuminuria, ␮g/24 h
db/db
db/m
Age 8 wk
Age 12 wk
Age 16 wk
247 ⫾ 41*
249 ⫾ 34*
303 ⫾ 30*
6⫾3
4⫾2
21 ⫾ 8
Age 21–25 wk
214 ⫾ 44*
10 ⫾ 2.5
Albuminuria, ␮g Alb/␮g Crt
Ref. no.
4
4
4
14
db/db
db/m
Ref. no.
1.47 ⫾ 0.37*
1.53 ⫾ 0.44*
0.91 ⫾ 0.29*
2.40 ⫾ 0.6*
2.39 ⫾ 0.35*
0.075 ⫾ 0.03
0.07 ⫾ 0.03
0.069 ⫾ 0.01
0.12 ⫾ 0.06
0.054 ⫾ 0.02
9
9
9
35
9
Values are means ⫾ SE. Alb, albumin; Crt, creatinine. * P ⬍ 0.05 vs. corresponding value for control group.
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value found by the Jaffé reaction in normal mice (27).
Similar results were found in db/db mice (Sharma and
Dunn, unpublished observations). The increased concentration as measured by the Jaffé reaction is thought
to be due to the presence of yet unidentified noncreatinine chromagens present exclusively in mouse blood.
Although several modifications of the Jaffé reaction
have been touted to be more specific (7, 26, 31, 33),
these measurements have not been performed compared with HPLC. Presently, HPLC with either spectrophotometric (UV detection) or HPLC coupled to a
mass spectrometer appears to be the definitive method
to measure creatinine in mouse plasma or serum.
Therefore, it is unclear what the endogenous creatinine
clearance signifies in relation to renal function. Nevertheless, as prior studies have found that db/db mice do
have an increase in serum creatinine after the age of 16
wk (4, 35) and db/db mice older than 17 wk of age do
have a decline in GFR (8), it may well prove correct
that the true endogenous creatinine clearance reflects
renal function. Formal studies comparing creatinine
clearance by HPLC-based methods with inulin-based
GFR methods are presently underway to address this
issue in diabetic mice.
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The role of antifibrotic approaches to inhibit progression of diabetic kidney disease has also been demonstrated using the db/db mouse. The db/db mouse exhibits an increase in glomerular transforming growth
factor-␤1 (TGF-␤1) as well as an increase in the type II
receptor for TGF-␤ (11). Inhibiting TGF-␤, with antiTGF-␤ antibodies, normalizes mesangial matrix accumulation, gene expression for type IV collagen, and
fibronectin, as well as renal functional parameters
(35). Interestingly, a recent study by Ziyadeh’s group
(2) found that mesangial matrix changes in the db/db
mouse appear to be reversible, as treatment of db/db
mice with established disease decreased the extent of
the lesions. The benefit of anti-TGF-␤ antibodies was
found without a reduction in albuminuria in the
treated mice (35), suggesting that an anti-TGF-␤ approach may be beneficial even without affecting albuminuria. In large part due to the beneficial effect of
inhibitors of various pathways in the db/db mice, approaches to block glycated proteins, PKC-␤ activation,
TGF-␤ action, and renal fibrosis are presently being
considered as novel treatment strategies for human
diabetic nephropathy.
In summary, the db/db mouse has a long history as a
model of human diabetic nephropathy. Key common
features with the human condition are renal hypertrophy, glomerular enlargement, albuminuria, and mesangial matrix expansion. Occasionally, arteriolar hyalinosis is observed in the glomerular arterioles. Features that are not as reproducibly altered in the db/db
mouse with respect to the human condition are the
increase in GBM thickening in relation to albuminuria
and the lack of progressive increase in albuminuria.
Features that are not observed in the db/db mouse are
the advanced features of diabetic nephropathy, such as
nodular sclerosis in the glomeruli, tubulointerstitial
fibrosis, and tubular atrophy. Features that may be
inconsistent with human diabetic nephropathy include
immune complex deposition in the glomerulus and
nodular thickening of the subepithelial space. Improved methods to assess kidney function in the db/db
mice are required to establish the extent of renal functional deterioration with duration of diabetes. Additional studies to examine the mechanisms underlying
the development of glomerular hypertrophy, albuminuria, and mesangial matrix expansion in the db/db
mouse could provide important insight and are likely
to be of relevance to the development of human diabetic
nephropathy.
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