Vol. 284, Issue 6, F1138-F1144, June 2003
INVITED REVIEW
Diabetic kidney disease in the db/db
mouse
Kumar
Sharma1,
Peter
McCue2, and
Stephen R.
Dunn1
1 Dorrance Hamilton Research Laboratory, Division of
Nephrology, Department of Medicine, and 2 Department of
Anatomy, Cell Biology and Pathology, Thomas Jefferson University,
Philadelphia, Pennsylvania 19107
 |
ABSTRACT |
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.
diabetic nephropathy; creatinine; albuminuria; mesangial
matrix
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INTRODUCTION |
THE
db/db MOUSE 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 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 associated 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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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.
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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 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.
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GLOMERULAR PATHOLOGY |
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. 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 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, formal quantitative
studies have not been published to establish the degree of GBM
thickening.
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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-µm sections were
stained with periodic acid-Schiff. Images are taken at ×400
magnification.
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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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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.
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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
discernable. 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.
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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
µl · min
1 · mouse1
in the control mice, whereas the GFR was ~700
µl · min1 · mouse1
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 µl · min1 · mouse1
(4), whereas the GFR was ~300
µl · min1 · mouse1
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 µmol/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 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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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 µg/24 h in the
db/db male mouse, whereas it is between 4 and 21 µg/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)
(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.
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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.
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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).
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 anti-TGF- 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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FOOTNOTES |
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{at}mail.tju.edu).
10.1152/ajprenal.00315.2002
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