1 Departments of Internal Medicine, 2 Cell Biology and Physiology, and 3 Pathology, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, Missouri 63110-1092
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ABSTRACT |
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Angiotensin II upregulates tumor
necrosis factor- (TNF-
) in the rat kidney with unilateral
ureteral obstruction (UUO). In a mouse model of UUO, we found that
tubulointerstitial fibrosis is blunted when the TNF-
receptor,
TNFR1, is functionally knocked out. In this study, we used mutant mice
with UUO in which the angiotensin II receptor AT1a or the
TNF-
receptors TNFR1 and TNFR2 were knocked out to elucidate
interactions between the two systems. The contribution of both systems
to renal fibrosis was assessed by treating TNFR1/TNFR2-double knockout
(KO) mice with an angiotensin-converting enzyme inhibitor, enalapril.
The increased interstitial volume (Vvint) in the C57BI/6
wild-type mouse was decreased in the AT1a KO from 32.8 ± 4.0 to 21.0 ± 3.7% (P < 0.005) or in the
TNFR1/TNFR2 KO to 22.3 ± 2.1% (P < 0.005). The Vvint of the TNFR1/TNFR2 KO was further
decreased to 15.2 ± 3.7% (P < 0.01) by
enalapril compared with no treatment. The induction of TNF-
mRNA and
transforming growth factor-
1 (TGF-
1) mRNA in the kidney with UUO
was significantly blunted in the AT1a or TNFR1/TNFR2 KO
mice compared with the wild-type mice. Treatment of the TNFR1/TNFR2 KO
mouse with enalapril reduced both TNF-
and TGF-
1 mRNA and their
proteins to near normal levels. Also,
-smooth muscle actin
expression and myofibroblast proliferation were significantly inhibited
in the AT1a or TNFR1/TNFR2 KO mice, and they were further
inhibited in enalapril-treated TNFR1/TNFR2 KO mice. Incapacitating
the angiotensin II or the TNF-
systems individually leads to partial
blunting of fibrosis. Incapacitating both systems, by using a
combination of genetic and pharmacological means, further inhibited
interstitial fibrosis and tubule atrophy in obstructive nephropathy.
interstitial volume; myofibroblast; tubulointerstitial fibrosis
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INTRODUCTION |
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A WIDE VARIETY OF RENAL DISEASES, regardless of etiology, lead to fibrosis of the tubulointerstitium compartment (4, 18). An increased intrarenal production of angiotensin II is widely considered the major causative factor that initiates and subsequently impels the progression of tubulointerstitial fibrosis (14, 15). We have used a rodent model of unilateral ureteral obstruction (UUO) to study the molecular and cellular mechanisms underlying renal fibrosis to develop therapeutic approaches to decrease or halt the progression of renal disease. Previous studies by our laboratory (9, 13) and those by others (2) have clearly documented that angiotensin II affects both renal epithelial cells and renal fibroblasts, primarily through the AT1 receptor. Additional studies indicate that the effects of angiotensin II, through the angiotensin II type 2 (AT2) receptor, also contribute to the development and progression of renal fibrosis (16, 17).
Angiotensin II promotes the synthesis of several cytokines and growth
factors that, in turn, contribute to the progression of renal fibrosis
(14, 15). In a previous study, we found that tumor
necrosis factor- (TNF-
) expression is increased in a rat model of
UUO (12). The induction of TNF-
mRNA at early times (4 h) was sensitive to angiotensin-converting enzyme (ACE) inhibition, but
this sensitivity was lost at latter times (5 days) (12).
In a recent study, by using a mouse model of UUO, we have shown that
the effects of TNF-
, related to renal fibrosis, are mediated through
both the TNFR1 and TNFR2 receptors, with the TNFR1 receptor playing a
predominating role (6).
In the present study, we utilized a combination of genetic knockout and
"pharmacological knockout" in the mouse model of UUO to examine the
pathways involved in renal fibrosis. Mice in which both the TNFR1 and
TNFR2 receptors had been genetically eliminated were treated with
enalapril to functionally eliminate angiotensin II-mediated effects.
The impact of this combined genetic-pharmacological approach was then
assessed to determine whether factors other than angiotensin II and
TNF- affect the initiation and progression of renal fibrosis.
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MATERIALS AND METHODS |
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Animals and experimental protocols.
Mice in which both of the TNF- receptors (TNFR1 and TNFR2) or the
AT1a receptor had been genetically knocked out, and C57BI/6 background mice were used in these experiments. Experimental protocols were approved by the Animal Care Committee of Washington
University School of Medicine. Wild-type C57BI/6 mice were obtained
from the Jackson Laboratory (Bar Harbor, ME), whereas the
double-knockout mice were a product of our own breeding program.
Breeder mice in which the AT1a receptor had been
genetically knocked out were a generous gift from Iekuni Ichikawa.
These mice were further bred into the C57BI/6 background. All animals
underwent surgical procedures designed to produce UUO, as described
previously (6, 9, 13). All animals were fed a standard
rodent chow and had free access to water. Some animals received 200 mg/l of enalapril in the drinking water for the duration of the UUO.
Animals were killed under pentobarbital anesthesia after 5 days of
ureteral obstruction, and the kidneys were perfused with an ice-cold
balanced salt solution to remove bloodborne cells. The kidneys were
quickly removed, a 2-mm coronal slice was placed in the fixative Histo choice (Amresco, Solon, OH), and the remaining cortex was rapidly dissected and homogenized to prepare total RNA (6).
Morphometric analysis of the interstitial volume, collagen IV,
and -smooth muscle actin matrix score and electron microscopy.
A standard point-counting method (6, 9, 13) was used to
quantitate the volume of the renal interstitium. The relative volume of
the renal cortical interstitium (Vvint) was determined on
sections by using an antibody to collagen IV to stain fibers in tubular
basement membrane (TBM), glomeruli, and the interstitial space. The
matrix score for
-SMA expression in the renal cortical interstitium
was determined by procedures well established in our laboratory, as
described previously (6, 9). Ten separate, nonoverlapping
microscopic fields of each kidney section were averaged to yield the
score of each kidney. The scores for five to nine separate animals for
each genotype and treatment modality were then averaged.
Messenger RNA quantitation.
Total RNA (2 or 4 ug) was used to prepare cDNA as in earlier studies
(6, 9, 13). The amount of mRNA for TNF- and transforming growth factor-
1 (TGF-
1) was determined by using primers and protocols described previously for reverse transcription, followed by PCR of the cDNA (11, 12). To quantitate PCR
products and to confirm the integrity of the RNA preparation, we
coamplified a housekeeping gene, glyceraldehyde-3-phosphate
dehydrogenase (GAPDH), in companion tubes. The PCR products of GAPDH,
TGF-
1, and TNF-
were electrophoresed in the same gel to eliminate
gel-to-gel or film-to-film variance. Dideoxy-chain termination
sequencing of the PCR products confirmed that indeed TNF-
, TGF-
1,
and GAPDH mRNA were amplified.
ELISA assays for TNF- and TGF-
1.
Portions of each kidney pole comprising cortex were rapidly homogenized
in 4 vol of ice-cold buffer containing 10 mM HEPES, pH 7.9, 0.1 mM
EGTA, 1 mM dithiothreitol, and a protease inhibitor cocktail for
mammalian tissues (P8340, Sigma, St. Louis, MO). The homogenate was
centrifuged at 3,000 g for 15 min at 4°C. The supernatants
were stored at
70°C until time of assay. On thawing of the protein,
content (Bio-Rad assays, Bio-Rad, Richmond, CA) was adjusted to 1.5 mg/ml with additional homogenization buffer.
Statistics.
Data, shown as means ± SD, were analyzed by the unpaired
t-test. Comparisons between values for the contralateral and
obstructed kidneys were performed by using an paired t-test.
ANOVA was employed to determine the significance of the
Vvint, collagen IV, or -SMA matrix score, TNF-
or
TGF-
1 mRNA.
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RESULTS |
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Interstitial volume.
Ligation of the ureter leads to a progressive interstitial fibrosis of
the obstructed kidney that develops in a matter of days. The
Vvint of the kidney increases due to a combination of fibroblast proliferation, monocyte/macrophage infiltration, and excessive matrix protein deposition (3, 13). This is
illustrated in Fig. 1, which depicts
sections of renal cortex that have been evaluated for collagen IV by
immunohistochemical means. In general, collagen IV is found in the
basement membrane surrounding tubules, peritubular capillaries, and
Bowman's capsule (Fig. 1, contralateral). The immunohistochemical
location of collagen IV was indistinguishable in the contralateral
kidneys of the C57BI/6 wild-type, the AT1a knockout, or the
TNFR1 and TNFR2 double knockout mice (not shown). When a standardized
point grid was superimposed over digitized images of magnified renal
cortex that was processed for the location of collagen IV, it was seen
that obstruction of the ureter caused a significant increase in the
number of points (circled in Fig. 1) that appear over the interstitium
(Fig. 1, contralateral C57BI/6 vs. obstructed C57BI/6). Ureteric
obstruction of the kidney of the TNFR1 and TNFR2 double knockout mouse
in the C57BI/6 background also produced an increase in the collagen IV
appearing in the interstitium, but not, however, to the extent of that
seen in the wild-type mouse. Enalapril treatment of the double knockout mice slightly, but significantly, decreased the amount of collagen IV
found in the interstitium after 5 days of UUO. These results and those
of the AT1a knockout mice are summarized in Fig.
2. Obstruction of the ureter led to a
470% increase of the Vvint of the wild-type mouse kidney
(Fig. 2). Enalapril treatment of wild-type C57BI/6 mice blunted this
increase of the interstitial volume to ~300%. The absence of a
functional AT1a receptor in C57BI/6 mice also had an
ameliorative effect on the increase in the Vvint, and ACE
inhibitor treatment had no significant effect in the AT1a
knockout mice (Fig. 2). Functional knockout of both TNF- receptors
was also associated with a blunted increase in the Vvint.
Enalapril treatment of the TNFR1 and TNFR2 double knockout mice led to
a further reduction (P < 0.01) of the
Vvint, compared with no treatment. The Vvint
increased only 180% above that seen in the contralateral kidneys
(P < 0.01). This residual increase in the
Vvint in the face of pharmacological knockout of
angiotensin II formation and genetic knockout of TNF-
action was
significant, compared with the contralateral kidney (P < 0.03).
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-SMA matrix score.
Another index of interstitial fibrosis of the tubulointerstitium in
renal disease is the differentiation of the fibroblast to a
myofibroblast (3, 9). This may be quantitiated by the immunohistochemical determination of
-SMA. Figure
3 depicts the same microscopic sections
of kidney as those seen in Fig. 1. These sections had been double
stained for collagen IV (Fig. 1) and for
-SMA (Fig. 3). In the
normal kidney (not shown) or the contralateral kidney of mice with UUO,
-SMA is largely, if not exclusively, confined to the arteries and
small vessels. In the kidney with an obstructed ureter, the
-SMA is
also present in the widened interstitium (Fig. 3, obstructed panels) as
well as in the blood vessels. It is seen that there is less
-SMA in
the interstitial space of the kidney in the sections obtained from the
TNFR1 and TNFR2 double knockout mouse and even less when these mice
were treated with enalapril. The results of several individual animals of each genotype and treatment are summarized in Fig.
4. The mean
-SMA score of the
contralateral kidneys was indistinguishable from kidneys of normal mice
and averaged 0.12 ± 0.04 (Fig. 4). Obstruction of the ureter led
to a significant increase in the
-SMA score to 2.42 ± 0.17 (n = 9) in the kidney cortex of the wild-type C57BI/6
mice. Enalapril treatment decreased the
-SMA matrix score by ~40%
to 1.44 ± 0.19. As was seen with the Vvint, the
absence of a functional AT1a receptor and ACE inhibitor
treatment also significantly decreased the matrix score from that of
the wild-type animals. There was no difference in the renal cortical matrix score of the AT1a knockout mouse of animals treated
or not treated with enalapril (n = 6). Absence of
functional TNFR1 and TNFR2 receptors also led to a significant
reduction in the
-SMA matrix score of the ureteral obstructed
kidneys. Enalapril treatment of these double knockout animals, however,
led to a further reduction in the matrix score for
-SMA to 0.81 ± 0.12, which is significant (P < 0.01) compared with
the score of 1.35 ± 0.20 in the nine untreated animals
(n = 7 for each). This residual matrix score in the ACE
inhibitor-treated double knockout mouse was still significantly greater
(P < 0.01) compared with the contralateral kidney
(Fig. 4).
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Electron microscopy.
Figure 1 shows that in the contralateral kidney there is a close
juxtaposition of the tubules and the peritubular capillaries. This
close apposition of capillaries to the tubule is disrupted in the
kidney with an obstructed ureter by cellular elements and by collagen
IV now appearing as a matrix protein (Fig. 1). In a previous study, we
showed that collagen types I and III are also deposited in the widened
interstitium, adding to the matrix proteins that disrupt the
interstitium, (11). Electron microscopic examination of
the renal cortex of the contralateral unobstructed kidney also
demonstrates abutment of the basement membranes of proximal tubules and
the close proximity of peritubular capillaries to these tubules (Fig.
5A).
Peritubular capillaries are surrounded by their own basement membranes
(small arrows in Fig. 5A). An occasional fibroblast is
present in the interstitial space outside the basement membranes (large
arrow in Fig. 5A). The cortical interstitium of the kidney
with an obstructed ureter is widened and contains an occasional
trilobed inflammatory cell (Fig. 5B) along with several
fibroblast-like cells (Fig. 5, B and C). The peritubular capillary (small arrows, Fig. 5, B and
C) are still surrounded by their basement membrane but are
separated from the tubules. In the mouse model of UUO in the C57BI/6
strain, there are few inflammatory cells in the interstitium at 5 days
of ureter obstruction (Morrissey J, unpublished observations). A survey of eight electron microscopic fields (×4,400-7,700) of
contralateral kidneys and 22 fields of the same power from kidneys with
an obstructed ureter indicates that in our mouse model, the major
cellular elements occupying the interstitium at 5 days of UUO are
fibroblasts. From Fig. 3, it is apparent that these fibroblasts contain
-SMA and have differentiated to myofibroblasts.
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TNF- and TGF-
1 mRNA levels.
Angiotensin II initiates an increase in the renal production of several
cytokines and growth factors, which then contribute to the progression
of renal fibrosis. Principal factors in the progression of renal
disease are TNF-
and TGF-
1 (6, 14, 15). In general,
the amount of GAPDH mRNA measured in the total RNA purified from the
renal cortex was invariant regardless of the genotype, treatment of the
mouse, or kidney of the mouse (not shown). Also, in general, the level
of either TNF-
or TGF-
1 mRNA in the contralateral kidney of the
mice was invariant (not shown) but consistent with the relative level
shown in the second lane from the left for both TNF-
or TGF-
1
mRNA. Depending on the genotype or treatment, the level of TNF-
or
TGF-
1 mRNA varied in the kidney with an obstructed ureter (Figs. 6
and 7). This is summarized for several animals in each group in Fig.
6 for TNF-
or in Fig.
7 for TGF-
1 mRNA. The salient
feature of the combination of TNF-
receptor genetic knockout and
angiotensin II "pharmacological knockout" is that the amount of
TNF-
or TGF-
1 mRNA is statistically indistinguishable from the
levels seen in the contralateral kidneys (Figs. 6 and 7). Importantly,
the levels of TGF-
1 mRNA were not increased in the kidney of the
AT1a knockout animals with an obstructed ureter (Fig. 7).
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TNF- and TGF-
1 protein levels.
The amount of TNF-
and TGF-
1 protein measured by ELISA methods
(Table 1) generally reflected the mRNA
levels seen in Figs. 6 and 7. With an intact TNF-
signaling system,
enalapril treatment inhibited TNF-
production by ~24-25% in
the wild-type or AT1a knockout mice. With knockout of the
TNF-
receptors, however, enalapril was ~93% effective above
baseline at inhibiting TNF-
production in the kidney with an
obstructed ureter, compared with the contralateral unobstructed
kidneys. The basal level of TNF-
in the contralateral kidneys was
independent of genotype and enalapril treatment. This suggests that
inactivation of both systems is required to substantially reduce
TNF-
production.
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DISCUSSION |
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In this study, we clearly show that both angiotensin II and
TNF- contribute to renal fibrosis in the mouse model of ureteral obstruction. These conclusions are based on both the genetic knockout of the TNF-
receptors and the AT1a receptor and the
pharmacological knockout of angiotensin II generation.
In the presence of enalapril, in AT1a knockout mice, the
contribution of angiotensin II through the AT2 receptor
should be minimized. In the AT1a knockout mice treated with
enalapril, there was a significant amount of TNF- generation. In the
TNFR1/2 knockout mouse, enalapril treatment significantly reduced
TNF-
mRNA and protein. This suggests that in the absence of
angiotensin II signaling, but in the presence of TNF-
signaling
(AT1a knockout mouse), the TNF-
system is contributing
to the increase in interstitial volume and
-SMA matrix score. This
also suggests that the TNF-
system is somewhat independent of the
angiotensin II system and contributes to renal fibrosis. When the
angiotensin II system plus the TNF-
system are simultaneously
incapacitated, both TNF-
and TGF-
1 levels are reduced to levels
indistinguishable from the levels seen in the contralateral kidneys.
The residual interstitial volume, collagen IV matrix score, and
-SMA
matrix score present in enalapril-treated TNFR1/2 knockout mice is
still significantly above that seen in the contralateral kidneys. The
results seen in the AT1a knockout mice or mice treated with
enalapril suggest that the TGF-
1 system is mainly driven by the
angiotensin II system. The TNF-
system appears to be driven by both
angiotensin II and by the presence of it's own intact receptors.
The dose of enalapril given is in excess of that thought to be
necessary to inhibit angiotensin II formation (10, 19). Regardless of arguments of the effectiveness of enalapril to inhibit ACE activity and, consequently, angiotensin II concentration, the
absence of an AT1a receptor in the knockout mice
incapacitates the angiotensin II system signaling through this
receptor. In the absence of AT1a signaling, TGF-1 mRNA
and protein are substantially decreased but TNF-
mRNA and protein
are only modestly reduced.
It has been recognized that in some models of renal disease, higher
doses of ACE inhibitors than that needed to blunt angiotensin II
formation have an additional beneficial effect (10, 19). In the absence of functional TNF- signaling systems, and in the presence of excessive ACE inhibitor treatment, there remains a significant residual of interstitial fibrosis. This suggests that other
vasoactive/growth factor systems contribute, in part, to the initiation
and progression of tubulointerstitial damage because both TGF-
1 and
TNF-
mRNA and protein levels were decreased to amounts statistically
indistinguishable from those levels found in the unobstructed
contralateral kidney.
At this point we cannot say whether the myofibroblasts arise by proliferation of the occasional fibroblast seen in the interstitium (Fig. 5A) or by epithelial-mesenchymal transdifferentiation. From Figs. 1 and 5, B and C, it is also apparent that there are many areas of interstitium containing fibrillar protein. How these fibrillar protein depositions (presumably collagens) affect fluid and solute reabsorption per se is not known; however, their presence is presumed to decrease the efficiency of transport processes. Regardless of the genotype of the animal (i.e., AT1a or TNFR1/2 knockout), the proportion of myofibroblasts and matrix protein in the widened interstitium of the kidney with an obstructed ureter was essentially the same.
An increase in renal angiotensin II levels is thought to be a major
factor in the initiation of a cascade of events leading to fibrotic
changes in the kidney (14, 15). The initial increase in
angiotensin II, in turn, causes upregulation of several vasoactive substances, cytokines, and growth factors (14, 15). This
secondary increase in profibrotic substances probably fuels the
progression of renal fibrosis. After angiotensin II initiates an
increased production of other vasoactive substances or growth factors,
a decrease in angiotensin II through pharmacological treatment may or
may not be effective in slowing the progression of renal disease. This
may lead to irreversible steps in renal fibrotic disease that are now
refractory to ACE inhibitor treatment. In this study, we found that
when the contributions of angiotensin II and TNF- are minimized, if
not entirely eliminated, there are other undefined factors that appear
to contribute to renal fibrosis. Studies from our own laboratory have
focused on the involvement of TNF-
(6, 14).
Interestingly, in the AT1a receptor knockout mice, the induction of TGF-
1 mRNA or TGF-
protein was significantly and substantially eliminated (Fig. 6 and Table 1). The model of renal disease resulting from UUO appears to be confined to the
tubulointerstitial compartment of the kidney until late in the
progression of disease (9). The lack of TGF-
1 mRNA
induction in the AT1a knockout mouse is supported by the
studies of Hisada and co-workers (7) using similar gene
knockout mice in a model of antiglomerular basement membrane disease.
This strongly suggests that the AT1b receptor that is
present is not linked to pathological fibrosis with respect to
induction of the profibrotic TGF-
1. However, the AT1b
receptor may be linked to the induction of other profibrotic factors
because hallmarks of disease such as
-SMA and increased interstitial
volume were reduced by only about half. A previous study using knockout
or transgenic mice for the angiotensinogen gene suggested that
angiotensin II accounted for ~60% of renal fibrosis.
(5).
A candidate system that has been suggested as a contributor to renal disease is the endothelin family. Originally described as vasoactive factors, endothelins appear to exacerbate renal damage in a model of passive Heymann nephritis (1, 20). In addition, overexpression of human endothelin-1 by transgenic mice was found to result in injury to both the glomerular and tubulointerstitial compartments of the kidney (8). A combination of angiotensin II and endothelin-1 blockade was recently suggested for renoprotection of patients who did not respond solely to ACE inhibitors (1).
In summary, these studies suggest that each of the different growth
factor/cytokine systems contributes to the initiation and progression
of renal disease that culminates in fibrosis. The angiotensin II system
appears to be a major driving force in the development of fibrotic
renal disease. The TNF- system is also involved in fibrotic renal
disease. About 20-30% of renal fibrosis appears to be driven by
at least one other, if not more, renal growth factor/cytokine systems.
This suggests that a multipharmacological approach is necessary to halt
renal disease progression. Whereas some systems may be initially
responsive to ACE inhibitor treatment, these systems may subsequently
become refractory. This suggests that treatment may need to be tailored
during the different stages of the disease.
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ACKNOWLEDGEMENTS |
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The assistance of Monica Waller and Rosalie Dustmann in the preparation of this manuscript is greatly appreciated.
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FOOTNOTES |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Program Project Grant DK-09976.
Address for reprint requests and other correspondence: J. Morrissey, Washington Univ. School of Medicine at Barnes-Jewish Hospital (North Campus), 216 S. Kingshighway Blvd., St. Louis, MO 63110-1092 (E-mail:morrisse{at}imgate.wustl.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 31 May 2000; accepted in final form 18 December 2000.
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