Role of TNFR1 and TNFR2 receptors in tubulointerstitial
fibrosis of obstructive nephropathy
Guangjie
Guo,
Jeremiah
Morrissey,
Ruth
McCracken,
Timothy
Tolley, and
Saulo
Klahr
Department of Internal Medicine and the Department of Cell Biology
and Physiology, Washington University School of Medicine at
Barnes-Jewish Hospital, St. Louis, Missouri 63110-1092
 |
ABSTRACT |
Unilateral ureteral obstruction (UUO) results in
tubulointerstitial fibrosis of the obstructed kidney. In
this study, we report the contribution of tumor necrosis factor-
(TNF-
) to the fibrosis that develops after ureteral obstruction.
Mice in which individual TNF-
receptors TNFR1 or TNFR2 had been
genetically knocked out were used, and results were compared with mice
of C57Bl/6 background after 5 days UUO. Both kidneys were removed and
examined histologically for changes in interstitial volume
(Vvint), collagen IV deposition,
-smooth muscle actin (
-SMA) matrix score, nuclear factor-
B (NF-
B) activity, and TNF-
mRNA levels. We found that the
Vvint of contralateral
unobstructed kidneys averaged ~7% and was indistinguishable among
the three genotypes of mice. Vvint
of ureteral obstructed kidney of C57Bl/6 mice averaged 33 ± 3.9%
after 5 days of UUO. Vvint of
obstructed kidneys of TNFR1 mice was significantly reduced to 19.4 ± 3.1%, whereas that of TNFR2 mice was significantly decreased to
25.4% ± 4.8%. There was a modest but significant difference between Vvint of TNFR1 and TNFR2
(P < 0.047). Both collagen IV and
-SMA matrix scores were decreased significantly in obstructed kidney
of TNFR1 mouse compared with that of C57Bl/6 and TNFR2 mice. Nuclear
extracts prepared from kidney cortex were found to have a significant
increase in NF-
B binding activity in obstructed kidney compared with
contralateral kidney. Individual knockout of the TNFR1 or TNFR2 genes
resulted in significantly less NF-
B activation compared with the
wild type, with TNFR1 being less than TNFR2 knockout. There was a
significant increase in TNF-
mRNA in the kidney with ureteral
obstruction in all three genotypes. TNFR1 knockout displayed a
significant reduction in amount of TNF-
mRNA induced compared with
wild-type or TNFR2 knockout mice. Treatment of TNFR1 knockout mice with
an angiotensin converting enzyme inhibitor further decreased
Vvint and TNF-
mRNA induction, suggesting an interaction of ANG II and TNF-
systems. These results suggest that TNF-
contributes, in part, to changes in interstitial volume, myofibroblast differentiation, and NF-
B activation in the
kidney during ureteral obstruction. These changes appear to be mediated
through both TNFR1 and TNFR2 gene products with effects through the
TNFR1 receptor predominating. Furthermore, ANG II appears to stimulate
TNF-
pathophysiological events leading to renal fibrosis.
tumor necrosis factor-
; chronic renal disease; myofibroblasts
 |
INTRODUCTION |
FIBROSIS of the tubulointerstitium compartment is a
major histological finding in kidney diseases of diverse etiology (17). Unilateral ureteral obstruction (UUO) is a well-established model of
experimental renal injury that results in changes in renal hemodynamics, infiltration of the kidney by macrophages, and subsequent fibrosis of the tubulointerstitium (14). Many of the pathophysiological alterations associated with renal disease are driven by the intercrine, autocrine, paracrine, and endocrine effects of angiotensin II.
Previous studies from our laboratory have demonstrated that angiotensin
II production is rapidly stimulated following the onset of ureteral
obstruction (6). Angiotensin II, in turn, upregulates the expression of
other factors including transforming growth factor-
(TGF-
) (10),
tumor necrosis factor-
(TNF-
) (12), nuclear factor-
B (NF-
B)
(21), adhesion molecules (22, 27), and chemoattractants (5, 22), matrix
proteins (11, 28), and
-smooth muscle actin (
-SMA) (8, 25). The
role of TNF-
in the pathophysiology of obstructive uropathy, when compared with angiotensin II, is not well understood. In rats, we have
previously used pharmacological maneuvers to inhibit angiotensin II
formation or its biological action through receptor inhibition (8, 11,
12, 15, 20, 21, 23). No such pharmacological treatments are available
to decipher the biological actions of TNF-
. Two different cell
surface receptors exist for TNF-
, which are designated TNFR1 and
TNFR2, that are derived from separate gene products (26).
In this study, we examined the contribution of TNF-
to the
pathophysiology of the interstitial fibrosis that occurs after UUO
using mice in which the known receptors for TNF-
have been individually deleted through genetic means. This would then allow us to
determine whether TNF-
is a contributory factor to the pathophysiology of obstructive nephropathy. The vast majority of
studies concerning tubulointerstitial fibrosis have utilized the rat
model. The power of genetics and the ability to manipulate the genetics
of the mouse cannot be ignored. Therefore, this study also serves to
provide a database for future studies in the mouse.
 |
MATERIALS AND METHODS |
Animals and experimental protocols.
Mice in which the individual TNF-
receptors, TNFR1 and TNFR2, had
been genetically knocked out and C57Bl/6 background mice were used in
these experiments. Experimental protocols were approved by the Animal
Care Committee of Washington University School of Medicine. We thank
Horst Bluethmann (TNFR1) and Genentech (TNFR2) for
permission to obtain these mice from Thomas Ferguson and Steven
Teitelbaum at Washington University School of Medicine. Wild-type
C57Bl/6 mice were obtained from the Jackson Laboratory (Bar Harbor, ME)
All animals underwent surgical procedures, designed to produce UUO, as
described previously (10, 11, 21, 22). 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 blood-borne cells. The kidneys were
quickly removed, a 2-mm coronal slice was placed in the fixative
Histochoice (Amresco, Solon, OH), and the remaining cortex was rapidly
dissected and homogenized to prepare total RNA (10, 11, 21, 22) or
nuclear extracts (21).
Morphometric analysis of the interstitial volume,
collagen IV, and
-SMA matrix score. A standard
point-counting method (8, 11, 21, 22) was used to quantitate the volume
of the renal interstitium. The relative volume (Vv) of the renal
cortical interstitium (Vvint) was
determined on sections using the Azan-Mallory method to stain collagen
fibers in tubular basement membrane (TBM), glomeruli, and the
interstitial space. The matrix score for collagen IV or
-SMA
expression in the renal cortical interstitium was determined by
procedures well established in our laboratory as described previously
(8, 11). Ten separate nonoverlapping microscopic fields of each kidney
section were averaged to yield the score of each kidney. The score for
six separate animals was then averaged.
mRNA quantitation. Total RNA (2 or 4 µg) was used to prepare cDNA as in earlier studies (8, 11). The
amount of mRNA for TNF-
was determined using primers and protocols
as described previously for RT-PCR of the cDNA (10). 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
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-
and GAPDH mRNA were amplified.
Electrophoretic mobility shift assay.
Crude nuclear extracts were prepared from kidney cortex as described
previously (21). Nuclear extracts were incubated with a radiolabeled
oligonucleotide representing a NF-
B sequence within the TNF-
promoter/enhancer essentially as described previously (15). Proteins
that bind to this oligonucleotide retard its migration in a
nondenaturing polyacrylamide gel. Location of these binding proteins
was determined by subjecting the dried gel to radioautography
using Kodak Biomax film.
Statistics. Data, shown as means ± SD, were analyzed by the unpaired
t-test. Comparisons between values for
the contralateral and obstructed kidneys were performed using a paired
t-test. ANOVA was employed to
determine the significance of the relative volume of the renal
interstitium (Vvint), collagen
IV or
-SMA matrix score.
 |
RESULTS |
Morphometric analysis of interstitial
volume. The relative volume of the cortical
interstitium was expressed as the volume fraction
(Vvint) (Fig.
1). UUO of 5 days duration resulted in a
significant increase (P < 0.001, n = 6) in the
Vvint of the ureteral obstructed
kidney (33 ± 3.9%) compared with the contralateral unobstructed
kidney (7%). The Vvint of the
obstructed kidneys of both the TNFR1 mice and the TNFR2 mice were
significantly reduced to 19.4 ± 3.1% and 25.4 ± 4.8%,
respectively. There was a slight but significant difference between the
TNFR1 and TNFR2 Vvint
(P < 0.047). No significant
difference was observed in the
Vvint of the contralateral
unobstructed kidney among the three genotypes.

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Fig. 1.
Fractional volume occupied by the interstitium
(Vvint) of the renal cortex
after 5 days of unilateral ureteral obstruction (UUO). Data are means ± SD of 6 animals of each genotype. TNFR1 and TNFR2, tumor necrosis
factor- (TNF- ) receptors 1 and 2; KO, knockout; Ob, obstructed
kidney; Ck, contralateral kidney.
|
|
Immunohistochemical studies on collagen IV and
-SMA
protein in the interstitium. Interstitial collagen IV
was evident in the obstructed kidney after 5 days of UUO compared with
the contralateral kidney of the C57Bl/6 mice (Fig.
2). Collagen IV was present in the TBM,
Bowman's capsule, and the mesangium in the contralateral kidney of the
mice. The obstructed kidney showed an increased deposition of collagen
IV protein, especially in the interstitial space. There was a greatly
reduced deposition of collagen IV protein in the interstitium of
kidneys with an obstructed ureter for 5 days in TNFR1 mice compared
with wild-type C57Bl/6 mice or TNFR2 mice (Fig. 2 and Table
1).

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Fig. 2.
Immunocytochemical localization of collagen type IV in renal cortex of
mice after 5 days of UUO. Representative photomicrographs of sections
of 6 animals of each genotype are depicted. Contralateral kidneys of
each genotype were indistinguishable from each other.
|
|
The protein
-SMA is expressed in the renal mesangium in a variety of
glomerular diseases (1). Previous studies from our laboratory and those
of others have detected the appearance of
-SMA in the widened
interstitial space during UUO (8, 23). In the contralateral
unobstructed kidney, the
-SMA was found only in arteries and
arterioles (Fig. 3). In the kidney with an obstructed ureter, there was a substantial amount of
-SMA within the
interstitium as well as in the blood vessels. The
-SMA actin matrix
score was reduced significantly in the obstructed kidney in TNFR1 mice,
compared with the C57Bl/6 and TNFR2 mice (Fig. 3 and Table 1).

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Fig. 3.
Immunocytochemical localization of -smooth muscle actin ( -SMA) in
renal cortex of mice after 5 days of UUO. Representative
photomicrographs of sections of kidneys of 6 animals of each genotype
are depicted. Contralateral kidneys of each genotype were
indistinguishable from each other. Microscopic fields are the same as
in Fig. 2.
|
|
The quantitative expression of collagen IV and
-SMA is shown in
Table 1. The expression of collagen IV in the obstructed kidney of
C57Bl/6 and TNFR2 mice revealed an average matrix score of 2.70 ± 0.07 and 2.20 ± 0.12, which was significantly reduced to
1.28 ± 0.08 in TNFR1 mice (P < 0.01). For
-SMA expression in the obstructed kidney, the matrix
score in C57Bl/6 and TNFR2 mice averaged 2.34 ± 0.09 and 1.84 ± 0.24. The
-SMA matrix score was significantly reduced to 1.16 ± 0.11 (P < 0.01) in the obstructed kidney of the TNFR1 mice.
Gel shift assay on the activity of
NF-
B.
Nuclear extracts obtained from the kidney cortex were subjected to
electrophoretic mobility shift assays using a
32P-labeled oligonucleotide
representing an NF-
B sequence found in the promoter/enhancer region
of the TNF-
gene (Fig. 4). Figure 4
shows that NF-
B activity was increased in the obstructed kidney compared with the contralateral kidney after 5 days of ureteral obstruction in all three genotypes of mice. Individual knockout of the
TNFR1 or TNFR2 genes resulted in significantly less NF-
B activation
compared with the wild type, with TNFR1 less than the TNFR2
knockout.

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Fig. 4.
Electrophoretic mobility shift assay of nuclear extracts that bind a
radiolabeled nuclear factor- B (NF- B)-like sequence present in the
TNF- gene promoter. Extracts were prepared from the cortex of each
kidney 5 days after UUO. Results are representative of nuclear extracts
of 4 animals of each genotype. N, nuclear extract of a normal kidney of
an unoperated C57Bl/6 mouse; C, nuclear extracts for the contralateral
kidney; O, nuclear extracts of the ureteral obstructed kidney. 0, no
nuclear extract present and depicts the migration of the labeled
oligonucleotide.
|
|
Expression of TNF-
mRNA during
UUO.
We have reported previously (12) that the ureteral obstructed kidney of
rats had a prominent increase of TNF-
mRNA level compared with the
contralateral kidney. We used the same technique of RT-PCR to examine
TNF-
mRNA expression among the three mouse genotypes. There was a
significant increase in TNF-
mRNA in the kidney with ureteral
obstruction in all three genotypes (Fig. 5). However, the TNFR1 knockout displayed
an obvious reduction in the amount of TNF-
mRNA induced compared
with the wild-type or the TNFR2 knockout mice. The expression of the
housekeeping gene GAPDH was not significantly different between the
three mouse genotypes or between the contralateral unobstructed or the
ureteral obstructed kidneys (Fig. 5). The amount of total RNA utilized to prepare the cDNA was constant. The combination of equal total RNA
and GAPDH cRNA amplification suggests that a real difference exists in
the ability to amplify TNF-
cDNA in the TNFR1 knockout compared with
the wild-type and TNFR2 knockout mouse.

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Fig. 5.
TNF- mRNA present in the cortex of each kidney 5 days after UUO.
These results are representative of the RT-PCR products of 4 animals of
each genotype. Amount of glyceraldehyde-3-phosphate dehydrogenase
(GAPDH) mRNA was also determined in companion RT-PCR.
Lane 1, no added cDNA in the PCR mix;
C, cDNA prepared from the contralateral kidney; O, cDNA prepared from
the ureteral obstructed kidney. Unmarked lanes represent the migration
of a 100-bp ladder of markers. C57, C57Bl/6 (wild type); R1KO, TNFR1
knockout; R2KO, TNFR2 knockout.
|
|
Role of the angiotensin system. The
present investigation is based on the premise that angiotensin II
formation upregulates TNF-
production (12). This was further tested
in this murine model by pretreating mice with enalapril and maintaining
this treatment for 5 days of UUO. In Fig.
6, it is seen that the angiotensin converting enzyme (ACE) inhibitor significantly decreased the interstitial volume expansion due to ligation of the ureter by ~36%
in the C57Bl/6 wild-type mouse kidney. In the TNFR1 knockout mice, the
interstitial volume expansion is significantly less than in the
wild-type mouse (compare Figs. 1 and 6). This was further decreased by
enalapril treatment to 12.3 ± 2.1%. This suggests that both
angiotensin II and TNF-
contribute to interstitial expansion in the
obstructed kidney.

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Fig. 6.
Fractional volume occupied by the interstitium
(Vvint) of the renal cortex
after 5 days of UUO without or with enalapril treatment. Data are means ± SD of 4 animals of each genotype and condition.
|
|
That inhibition of angiotensin II formation affects TNF-
mRNA
induction is demonstrated in Fig. 7.
Treatment of either the C57Bl/6 wild-type mice or the TNFR1 knockout
mice with enalapril significantly decreased the amount of TNF-
mRNA
(lanes 4 and 8). As seen in Fig. 5, the amount of
TNF-
mRNA induced by ureteral ligation in the TNFR1 knockout is
significantly less than in the wild-type mouse kidney (compare
lanes 2 and
6). The amount of GAPDH mRNA was
essentially the same regardless of the genotype or treatment (Fig. 7).

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Fig. 7.
TNF- mRNA present in the cortex of each kidney 5 days after UUO in
animals without (lanes 2,
3, 6,
and 7) or with
(lanes 4,
5, 8,
and 9) enalapril treatment.
|
|
 |
DISCUSSION |
TNF-
was found to be upregulated early during obstructive
nephropathy in an angiotensin II-dependent manner (12, 16). Two
different receptors for TNF-
binding have been described: one with a
molecular mass of 55 kDa (TNFR1) and the other with a molecular mass of
75 kDa (TNFR2) (26). The binding of TNF-
to the two receptors
initiates different physiological events. The biological actions of
TNF-
have been studied in a variety of cell systems, including
intrinsic renal cells. Reported actions of TNF-
on renal cells
include the activation of second messenger systems, transcription
factors, synthesis of cytokines, growth factors, receptors, cell
adhesion molecules, enzymes involved in the synthesis of other
inflammatory mediators, acute phase proteins, and major
histocompatibility complex proteins (26). Our previous study indicated
that the levels of TNF-
mRNA increased significantly in the
obstructed kidney after ureteral ligation compared with the
contralateral kidney of the same animals or to the control kidney of
normal rats (12). In this investigation, we used mice in which the
individual TNF-
receptors, TNFR1 and TNFR2, have been genetically
knocked out and compared results to mice of the C57Bl/6 background.
After 5 days of UUO, there was a significant increase in TNF-
mRNA
in the obstructed kidney in all three genotypes. Furthermore, the TNFR1
knockout displayed a significant decrease in the amount of TNF-
mRNA
induced compared with the wild-type or the TNFR2 knockout mice. In
contrast to our previous study in rats (12), ACE
inhibition significantly decreased TNF-
mRNA levels in
the mouse at 5 days of UUO. This may represent a species difference.
Previous studies have reported that the expansion of the renal
interstitium after ureteral obstruction is due to factors such as
excessive matrix proteins production (11, 28), fibroblast proliferation
(11), and monocyte/macrophage infiltration (8, 11). The relative volume
of the interstitium of the cortex in the contralateral kidneys was
indistinguishable among these three genotypes. The
Vvint of the obstructed kidneys of
the TNFR1 mice were significantly reduced compared with the obstructed
kidney of the wild-type mice. Although the
Vvint of TNFR2 mice was modestly reduced compared with the TNFR1 mice, this was still significant (P < 0.047). Enalapril treatment of
the TNFR1 knockout mice further decreased the interstitial volume
expansion, suggesting that angiotensin II and TNF-
systems interact
to promote renal fibrosis. A decrease in the
Vvint of the wild-type mouse
kidney due to ACE inhibition was also found (Fig. 6), which is
consistent with results found by Moriyama and coworkers (20) in the
BL6/C3H wild-type mouse. Using immunohistochemical techniques, we found
that the deposition of collagen IV and
-SMA protein was markedly
decreased in the obstructed kidney of the TNFR1 mice
compared with that of the C57Bl/6 or TNFR2 mice. This may be due to the
differences in the intrarenal levels between TNFR1 and TNFR2. Mulligan
et al. (24) demonstrated that anti-TNF-
or soluble recombinant human
TNFR1 blocked the induction of intercellular adhesion molecule 1, endothelial leukocyte adhesion molecule 1, and vascular adhesion
molecule 1 in nephrotoxic nephritis. There are also reports
indicating that the binding of TNF-
to a cell-surface receptor
causes intracellular metabolic changes that mediate apoptosis and
necrotic cell death (18, 19), although the exact mechanism of the
cytocidal action of TNF-
remains unclear. The TNFR1 receptor has a
sequence similar to the Fas antigen receptor in the cytoplasmic domain,
which is suggested to mediate apoptosis (9). Renal tubular cells in the
obstructed kidney undergo apoptosis 1-2 wk after ureteral ligation
(7, 13). Therefore, further studies remain to be done to determine
whether an increase of TNF-
in the obstructed kidney induces
apoptosis of tubular cells or causes tubular damage.
NF-
B has a role in the transcriptional regulation of a number of
genes in all tissues including kidney (2). It has two forms: an
inactive form located in the cell cytoplasm, complexed with an
inhibitor, and an active form that translocates to the nucleus. The
active forms are homodimers or heterodimers, composed of two proteins,
which are p50, p52, p65 (Rel A), relB, and c-rel (3). Many compounds
can activate NF-
B, inducing its translocation to the nucleus.
NF-
B is activated by angiotensin II through AT1 and AT2 receptors
during experimental ureteral obstruction (15). In addition, an ACE
inhibitor markedly decreases NF-
B activation in the kidney with
ureteral obstruction (21). We found that only the nuclear extracts from
the cortex of kidneys with an obstructed ureter contain proteins that
can bind to a NF-
B-like nucleotide sequence present in the rat
TNF-
gene promoter. Interestingly, TNF-
stimulates NF-
B
activation (4), which in turn creates an autocrine reinforcing loop of
TNF-
formation. That study confirms that nuclear extracts prepared
from the kidney cortex were found to have a significant increase in
NF-
B binding activity in the obstructed compared with the
contralateral kidney; this increase was found in all three mouse
genotypes. Furthermore, we found that individual knockout of the TNFR1
or the TNFR2 genes resulted in significantly less NF-
B activation
compared with the wild type, with TNFR1 less than the TNFR2 knockout.
The NF-
B isotypes (homodimer or heterodimer combinations) appear to
differ more greatly in the unobstructed kidney of the TNFR1 and TNFR2
mice than in the kidney of the C57Bl/6 wild-type mice. The
composition of these NF-
B binding proteins remains to be determined
but suggests that tonic forces in the contralateral kidney may be
different in the gene knockout mice. Our data show that in the
individual TNFR1 knockout mice, TNF-
mRNA levels and the activation
of NF-
B are significantly decreased compared with the gene
background and TNFR2 knockout mice. This coincides with the decreased
interstitium volume, matrix protein, and
-SMA expression. What is
not known, at present, is which NF-
B isotypes may be associated with
specific pathological events (fibroblast proliferation) or
counterregulatory beneficial events (antiapoptosis), since NF-
B
activation opposes TNF-
cytotoxicity (16).
In summary, the mouse model of ureteral obstruction recapitulates many
of the pathophysiological events that have been documented in the rat
which lead to renal fibrosis. This report demonstrates that TNF-
contributes, in part, to changes in interstitial volume, myofibroblast
differentiation, and NF-
B activation in the kidney during ureteral
obstruction. These changes appear to be mediated through both the TNFR1
and TNFR2 gene products, with effects through the TNFR1 predominating.
Furthermore, the angiotensin II and TNF-
systems appear to interact
with each system, contributing to overall renal fibrosis.
 |
ACKNOWLEDGEMENTS |
These studies were supported by National Institute of Diabetes
and Digestive and Kidney Diseases Program Project Grant
DK-09976.
 |
FOOTNOTES |
No reprints of this article are available.
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. §1734 solely to indicate this fact.
Address for correspondence: J. Morrissey, Department of Internal
Medicine, Washington University School of Medicine, at Barnes
Jewish Hospital (North Campus), 216 South Kingshighway Boulevard, Saint
Louis, MO 63110-1092 (E-mail:
morrisse{at}imgate.wustl.edu).
Received 28 January 1999; accepted in final form 30 June 1999.
 |
REFERENCES |
1.
Alpers, C. E.,
K. L. Hudkins,
A. M. Gown,
and
R. J. Johnson.
Enhanced expression of "muscle-specific" actin in glomerulonephritis.
Kidney Int.
41:
1134-1142,
1992[Medline].
2.
Baeuerle, P. A.,
and
T. Henkel.
Function and activation of NF-
B in the immune system.
Annu. Rev. Immunol.
12:
141-179,
1994[Medline].
3.
Barnes, P. J.,
and
M. Karin.
Nuclear factor-
B: a pivotal transcription factor in chronic inflammatory diseases.
N. Engl. J. Med.
336:
1066-1071,
1997[Free Full Text].
4.
Brasier, A. R.,
J. Li,
and
K. A. Wimbish.
Tumor necrosis factor activates angiotensinogen gene expression by the Rel A transactivator.
Hypertension
27:
1009-1017,
1996[Abstract/Free Full Text].
5.
Diamond, J. R.,
D. Kees-Folts,
G. Ding,
J. E. Frye,
and
N. C. Restrepo.
Macrophages, monocyte chemoattractant peptide-1, and TGF-
1 in experimental hydronephrosis.
Am. J. Physiol.
266 (Renal Fluid Electrolyte Physiol. 35):
F926-F933,
1994[Abstract/Free Full Text].
6.
El-Dahr, S. S.,
J. Gee,
S. Dipp,
B. G. Hanss,
R. C. Vari,
and
J. Chao.
Upregulation of renin-angiotensin system and downregulation of kallikrein in obstructive nephropathy.
Am. J. Physiol.
264 (Renal Fluid Electrolyte Physiol. 33):
F874-F881,
1993[Abstract/Free Full Text].
7.
Gobe, G. C.,
and
R. A. Axelsen.
Genesis of renal tubular atrophy in experimental hydronephrosis in the rat. Role of apoptosis.
Lab. Invest.
56:
273-281,
1987[Medline].
8.
Ishidoya, S.,
J. Morrissey,
R. McCracken,
A. Reyes,
and
S. Klahr.
Angiotensin II receptor antagonist ameliorates renal tubulointerstitial fibrosis caused by unilateral ureteral obstruction.
Kidney Int.
47:
1285-1294,
1995[Medline].
9.
Itoh, N.,
S. Yonehara,
A. Ishii,
M. Yonehara,
S. Mizushima,
M. Sameshima,
A. Hase,
Y. Seto,
and
S. Nagata.
The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis.
Cell
66:
233-243,
1991[Medline].
10.
Kaneto, H.,
J. Morrissey,
and
S. Klahr.
Increased expression of TGF-
1 mRNA in the obstructed kidney of rats with unilateral ureteral ligation.
Kidney Int.
44:
313-321,
1993[Medline].
11.
Kaneto, H.,
J. Morrissey,
R. McCracken,
A. Reyes,
and
S. Klahr.
Enalapril reduces collagen type IV synthesis and expansion of the interstitium in the obstructed rat kidney.
Kidney Int.
45:
1637-1647,
1994[Medline].
12.
Kaneto, H.,
J. J. Morrissey,
R. McCracken,
S. Ishidoya,
A. A. Reyes,
and
S. Klahr.
The expression of mRNA for tumor necrosis factor
increases in the obstructed kidney of rats soon after unilateral ureteral ligation.
Nephrologie
2:
161-166,
1996.
13.
Kennedy, W. A.,
A. Stenberg,
G. Lackgren,
T. W. Hensle,
and
I. S. Sawczuk.
Renal tubular apoptosis after partial ureteral obstruction.
J. Urol.
152:
658-664,
1994[Medline].
14.
Klahr, S.,
K. Harris,
and
M. L. Purkerson.
Effects of obstruction on renal functions.
Pediatr. Nephrol.
2:
34-42,
1988[Medline].
15.
Klahr, S.,
and
J. Morrissey.
Angiotensin II and gene expression in the kidney.
Am. J. Kidney Dis.
31:
171-176,
1998[Medline].
16.
Klahr, S.,
and
J. J. Morrissey.
The role of growth factors, cytokines and vasoactive compounds in obstructive nephropathy.
Semin. Nephrol.
18:
622-632,
1998[Medline].
17.
Kuncio, G. S.,
E. G. Neilson,
and
T. Haverty.
Mechanisms of tubulointerstitial fibrosis.
Kidney Int.
39:
550-556,
1991[Medline].
18.
Larrick, J. W.,
and
S. C. Wright.
Cytotoxic mechanism of tumor necrosis factor-
.
FASEB J.
4:
3215-3223,
1990[Abstract].
19.
Laster, S. M.,
J. G. Wood,
and
L. R. Gooding.
Tumor necrosis factor can induce both apoptic and necrotic forms of cell lysis.
J. Immunol.
141:
2629-2634,
1988[Abstract/Free Full Text].
20.
Moriyama, T.,
N. Kawada,
A. Ando,
A. Yamauchi,
M. Horio,
K. Nagata,
E. Imai,
and
M. Hori.
Up-regulation of HSP47 in the mouse kidneys with unilateral ureteral obstruction.
Kidney Int.
54:
110-119,
1998[Medline].
21.
Morrissey, J. J.,
and
S. Klahr.
Enalapril decreases nuclear factor
B activation in the kidney with ureteral obstruction.
Kidney Int.
52:
926-933,
1997[Medline].
22.
Morrissey, J. J.,
and
S. Klahr.
Differential effects of ACE and AT1 receptor inhibition on chemoattractant and adhesion molecule synthesis.
Am. J. Physiol.
274 (Renal Physiol. 43):
F580-F586,
1998[Abstract/Free Full Text].
23.
Morrissey, J. J.,
and
S. Klahr.
Effect of AT2 receptor blockade on the pathogenesis of renal fibrosis.
Am. J. Physiol.
276 (Renal Physiol. 45):
F39-F45,
1999[Abstract/Free Full Text].
24.
Mulligan, M. S.,
K. J. Johnson,
R. F. Todd,
T. B. Issekutz,
M. Miyasaka,
T. Tamatani,
C. W. Smith,
D. C. Anderson,
and
P. A. Ward.
Requirements for leukocyte adhesion molecules in nephrotoxic nephritis.
J. Clin. Invest.
91:
577-587,
1993[Medline].
25.
Nagle, R. B.,
M. R. Kneiser,
R. E. Bulger,
and
E. P. Benditt.
Induction of smooth muscle characteristics in renal interstitial fibroblasts during obstructive nephropathy.
Lab. Invest.
29:
422-427,
1973[Medline].
26.
Ortiz, A.,
C. Bustos,
J. Alonso,
R. Alcázar,
M. J. López-Armada,
J. J. Plaza,
E. González,
and
J. Egido.
Involvement of tumor necrosis factor-alpha in the pathogenesis of experimental, and human glomerulonephritis.
Adv. Nephrol. Necker Hosp.
24:
53-77,
1995[Medline].
27.
Ricardo, S. D.,
M. E. Levinson,
M. R. DeJoseph,
and
J. R. Diamond.
Expression of adhesion molecules in rat renal cortex during experimental hydronephrosis.
Kidney Int.
50:
2002-2010,
1996[Medline].
28.
Sharma, A. K.,
S. M. Mauer,
Y. Kim,
and
A. F. Michael.
Interstitial fibrosis in obstructive nephropathy.
Kidney Int.
44:
774-788,
1993[Medline].
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