Departments of 1 Internal Medicine and 2 Cell Biology and Physiology, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, Missouri 63110-1092
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ABSTRACT |
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Unilateral ureteral obstruction
(UUO) is a well-established model for the study of interstitial
fibrosis in the kidney. It has been shown that the renin-angiotensin
system plays a central role in the progression of interstitial
fibrosis. Recent studies indicate that endothelin, a powerful
vasoconstrictive peptide, may play an important role in some types of
renal disease. To investigate the effects of angiotensin II on
endothelin and its receptors in the kidney, mice were subjected to UUO
and treated with or without enalapril, an orally active
angiotensin-converting enzyme inhibitor, in their drinking water (100 mg/l). The animals were killed 5 days later. Using RT coupled with PCR,
we measured the levels of endothelin-1, endothelin A, and endothelin B
(ETB) along with transforming growth factor-, TNF-
,
and collagen type IV mRNA expression in the kidney with UUO and the
contralateral kidney along with interstitial expansion in the kidney
cortex by a standard point counting method. We found that enalapril
administration ameliorated the increased expression of ET-1 mRNA in the
obstructed kidney by 44% (P < 0.02). Although the
level of endothelin A mRNA expression was significantly increased in
the obstructed kidney, it was not affected by enalapril. We found that
enalapril treatment increased ETB mRNA expression by 115%
(P < 0.05) and protein expression (measured by Western
blot) in the kidney with an obstructed ureter. Enalapril treatment
alone inhibited the expansion of interstitial volume due to UUO by
52%. Cotreatment with enalapril and the ETB receptor
antagonist BQ-788 inhibited the expression of interstitial volume by
only 19%. This study confirms that enalapril inhibits the interstitial
fibrosis in UUO kidneys. It also suggests a beneficial and unforeseen
effect of enalapril on the obstructed kidney by potentially stimulating
the production of nitric oxide through an increased expression of the
ETB receptor.
nitric oxide formation; fibrosis; enalapril; angiotensin-converting enzyme; endothelin B receptor
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INTRODUCTION |
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TUBULOINTERSTITIAL
FIBROSIS develops in a variety of kidney diseases (29, 30,
33). Available data indicate that angiotensin II plays a central
role in the initiation and progression of renal disease by autocrine,
paracrine, intercrine, and endocrine pathways. Experimental ureteral
obstruction is a well-established model for the study of interstitial
fibrosis (20, 25, 26). Intrarenal concentrations of
angiotensin II increase rapidly after the onset of ureteral obstruction
in the ligated obstructed kidney (10). Angiotensin II, in
turn, upregulates the expression of transforming growth factor-
(TGF-
), TNF-
, and other growth factors and cytokines that lead to
the accumulation of ECM proteins and to renal damage (20-23,
28). We previously reported the beneficial effects of angiotensin-converting enzyme (ACE) inhibitor on the progression of
tubulointerstitial fibrosis in the UUO model (19-21, 23,
28). ACE inhibitors were found to blunt TGF-
and TNF-
expression concomitant with amelioration of histological changes that
occur in the kidney during disease. A more precise identification of these other factors that contribute to the initiation of and/or progression of kidney fibrosis is the subject of the study.
In the last decade, a number of studies have suggested that endothelin, a powerful vasoconstricting peptide (48), is also involved in the progression of chronic renal disease (2, 15, 31). Endothelin has at least three isopeptides: endothelin-1 (ET-1), endothelin-2 (ET-2), and endothelin-3 (ET-3) (18). Their effects are mediated through two different receptors: endothelin A (ETA), selective for ET-1 and ET-2, and endothelin B (ETB), nonselective to the three ET isopeptides (16, 46, 47). Among the three ETs, ET-1 appears to be the most important in pathophysiological conditions in the kidney. Indeed, it has been shown that renal tissue can synthesize and release ET-1 and also expresses both ETA and ETB receptors (3).
It has been shown in the last few years that angiotensin II can
stimulate the synthesis and release of ET-1 in endothelial cells or
vascular smooth muscle cells (7, 9, 12, 34, 44). However,
the role and interactions between angiotensin II and ET-1 in the
progression of renal fibrosis due to ureteral obstruction are still
unclear. Therefore, we used the ACE inhibitor enalapril to explore the
effects of angiotensin II on the mRNA expression of ET-1,
ETA, and ETB in mice with UUO. RT-PCR
was utilized for the semiquantitative analysis of mRNA. To confirm the
effects of enalapril, we also measured other cytokines, such as
TGF-, TNF-
, and collagen type IV mRNA, as a marker of ECM proteins and evaluated histological changes by using a standard point
counting method. This would validate any observed change(s) in
the pattern of endothelin gene expression. This would help to integrate
the contribution of the endothelin in the progression of renal disease
that probably was initiated by the increase in angiotensin II.
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MATERIALS AND METHODS |
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Animals and reagents. Female C57BL/6 mice (~25-30 g) were purchased from Harlan (Indianapolis, IN). Enalapril, BQ-788, and Tri Reagent, a reagent for RNA isolation, were supplied by Sigma (St. Louis, MO). Avian myeloblastosis virus reverse transcription kits and Taq polymerase were obtained from Promega (Madison, WI).
Experimental design. Initially, mice were divided into two groups: those receiving enalapril in the drinking water (100 mg/l; n = 9) and those receiving water alone as a control (n = 9). Each group was given water with or without enalapril from 1 day before obstruction of the ureter through 5 days of obstruction. Unilateral ureteral obstruction (UUO) was performed as described previously (19-23). In brief, a midline abdominal incision was made while the mice were under ketamine HCl and xylazine HCl (20:3; 87.0:13.4 mg/kg ip) anesthesia, and both ureters were exposed. The left ureter was ligated with 4-0 silk at one-third the distance from the bladder to the kidney. Animals were allowed to drink or eat normal rodent chow ad libitum after surgery. Subsequently, additional groups of mice were prepared to receive enalapril in the drinking water with or without daily injections (ip) of the ETB receptor antagonist BQ-788 at a dose of 1 mg/kg (48).
After 5 days of UUO, the mice were anesthetized with an overdose of ketamine HCl-xylazine HCl, and the kidneys were immediately harvested, decapsulated, and washed in ice-cold PBS. The kidneys were prepared for total RNA isolation and histological examination as described previously (19-23).Preparation of RNA. Total RNA was isolated from each kidney by the guanidinium-thiocyanate method (5). In brief, portions of the kidneys were homogenized in 1 ml of Tri Reagent. Total RNA was precipitated with isopropanol. The RNA pellets were washed in 75% ethanol, air dried, and dissolved in RNase-free distilled water. The quantitative analysis of total RNA was performed at 260 and 280 nm.
RT-PCR. Total RNA extracted from the kidneys was reverse transcribed into first-strand cDNA in RT buffer (10 mM Tris · HCl, 50 mM KCl, 5 mM MgCl2, 1 mM deoxynucleotide triphosphate mixture, and 1 U/µl RNase inhibitor), 0.5 U/µl avian myeloblastosis virus RT, and oligo(dT) primers. The incubation conditions (42°C for 1 h followed by 95°C for 5 min) were established by using a DNA Thermal Cycler (Perkin-Elmer).
PCR amplification was performed for ET-1, ETA, ETB, TGF-
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Relative quantitative analysis of mRNA. Products amplified by PCR were separated by 2.0% agarose gel containing ethidium bromide. The gels were visualized with UV light and were photographed with Polaroid Type 665 positive-negative films. The intensity of bands was measured by densitometry for quantification. The relative level of each mRNA was determined by normalizing the quantity of specific cDNA to the amount of GAPDH cDNA.
Relative quantitative analysis of ETB protein. Portions of kidney cortex were solubilized with Laemmli sample buffer by heating to 95°C for 5 min followed by brief centrifugation after cooling. The protein content of the supernatant was determined by Bradford assay and diluted to 2 mg/ml of sample. Twenty-five micrograms of total protein were separated by means of 10% acrylamide gels containing sodium dodecyl sulfate. Gel lanes containing kidney extracts were flanked by lanes containing prestained molecular mass markers. Proteins in the acrylamide gel were electrophoretically transferred to nitrocellulose membranes in Tris-glycine buffer containing 20% methanol with the prestained markers used as a guide for transfer efficiency. The location and relative amount of ETB antibody (1:100) were prepared in rabbit catalog no. AER-002 (Alomone Labs, Jerusalem, Israel) followed by a goat anti-rabbit IgG-horseradish peroxidase conjugate (Santa Cruz Biotechnology, Santa Cruz, CA) and Luminol reagent SC-2048. Similar results were obtained with an anti-rat ETB antibody 1:100 made in sheep (no. 324755, Calbiochem-Nova Biochem, San Diego, CA) and a donkey anti-sheep IgG-horseradish peroxidase conjugate (A3415, Sigma).
Immunohistochemical analysis. Coronal sections of kidney were placed in the fixative Histochoice (Amresco, Solon, OH). The sections were dehydrated, embedded in paraffin, cut into 4-µm sections, dewaxed, and rehydrated as described previously (41). The rehydrated sections were treated overnight at 4°C with 1:100 dilations of rabbit anti-rat ETB antibody (Alomone) followed by an alkaline phosphatase conjugated goat anti-rabbit IgG (A9919, Sigma) and evaluated with Sigma FAST-Fast Red/Naphthol (F4648).
Morphometric analysis. A standard point counting method was used to quantitate the volume of the renal interstitium (39). The relative volume of the renal cortical interstitium (Vv int) was determined on sections by using Mason-Trichrome stain. Ten separate nonoverlapping microscopic fields of each kidney section were averaged to yield the score of each kidney. Each microscopic field contained one glomerular cross section to maintain consistency. The score for 9-11 separate animals for each treatment modality was then averaged.
Statistical analysis. All data represent means ± SD. Intergroup comparisons were performed by ANOVA and Student's t-test. P < 0.05 was taken as the criterion of significance.
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RESULTS |
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RT-PCR.
We measured the expression of TGF-, TNF-
, and collagen IV mRNA in
mice with UUO with or without enalapril in the drinking water. This
served as a measure of the effectiveness of the enalapril treatment to
gauge any subsequent effects on endothelin gene family members.
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Morphometric analysis.
The relative volume of the cortical interstitium was expressed as
Vv int (Fig. 8). UUO of 5 days duration showed a significant increase (P < 0.001, n = 9) of Vv int in the
obstructed kidney (37.0 ± 1.1%) compared with the contralateral
kidney (6.0 ± 0.1%). This is consistent with our previous
studies (23, 41) and reflects what is observed in human
ureteral obstruction (39). Enalapril treatment
significantly ameliorated (P < 0.001) the increment by
52% in the kidneys with an obstructed ureter (23.7 ± 1.4%,
n = 11). No significant difference was observed between the contralateral kidneys of untreated mice and mice treated with enalapril. Other mice (n = 10) were treated with a
combination of oral enalapril and an intraperitoneal injection of the
ETB-specific receptor antagonist BQ-788 (48).
The decrease in interstitial volume due to enalapril treatment was
significantly (P < 0.001) blunted by the
ETB antagonism (Fig. 9) . There remained a significant decrease (P < 0.002)
between enalapril-BQ-788 cotreatment and untreated mice with UUO with
respect to the change in Vv int.
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DISCUSSION |
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In this study, we found that enalapril, an ACE inhibitor, blunted
the increased expression of ET-1 mRNA by 44% (P < 0.02) in the obstructed kidney. In the setting of UUO, the
renin-angiotensin system is upregulated (10). Angiotensin
II, in turn, stimulates the expression of TGF-, TNF-
, collagen
IV, and various cytokines or vasoactive compounds that play roles in
the progression of tubulointerstitial fibrosis (20-23,
28). We have previously shown that enalapril administration
blunted the increased expression of TGF-
and collagen IV mRNA in UUO
rats (19-21, 23). In this study, enalapril
significantly suppressed the increase of TGF-
mRNA in the kidney of
mice with an obstructed ureter. These data suggest that angiotensin II
either directly or indirectly upregulates ET-1 expression in the kidney
with an obstructed ureter. However, the fact that ET-1 mRNA expression
in the kidney with an obstructed ureter did not return to the normal
level because of ACE inhibition indicates the existence of other
factor(s) involved in the upregulation of ET-1 in the obstructed kidney.
Recently, Feldman et al. (11) reported on the levels of ETA and ETB mRNA expression in UUO rats at 5 days after the onset of obstruction. They showed that ETA mRNA expression was significantly elevated in the obstructed kidney compared with the contralateral kidney. The level of ETB mRNA expression was not affected by ureteral ligation. We obtained similar results in UUO mice with ureteral obstruction of the same duration. It seems there is not a difference between rats and mice concerning the expression or change of ETA and ETB mRNA in the model of UUO.
Enalapril administration had no effect on the expression of ETA mRNA in both kidneys when compared with those not receiving enalapril. Unexpectedly, enalapril administration increased the level of ETB mRNA expression by 115% (P < 0.02) and the amount of protein threefold (P < 0.001) in the obstructed kidney. This suggests the existence of a feedback system between ET-1 and its receptor ETB. Lehrke et al. (35) found that ACE inhibition decreases ETB expression in biopsy specimens obtained from patients with chronic renal disease. Our study is measuring more acute effects.
In addition to lowering angiotensin levels, ACE inhibitors affect kininase II and increase the levels of bradykinin (10), which in turn modulate nitric oxide production by the endothelial cells (36, 40, 52). Nitric oxide may have two opposite effects on renal disease. It is known that a moderate amount of nitric oxide is beneficial in the prevention of experimental renal disease (41). It has been reported that nitric oxide has a direct effect on matrix protein synthesis (32, 51). Our laboratory has previously shown an effect of nitric oxide on the prevention of interstitial fibrosis caused by UUO by the administration of L-arginine, a nitric oxide donor (41). On the basis of those data, we suggested that one of the reasons for the beneficial effects of enalapril was the increased production of nitric oxide modulated by the upregulated bradykinin in the kidney with an obstructed ureter. On the other hand, ET-1 has various biological effects and acts quite differently depending on its binding to two different types of receptors (4, 31). ET-1 can also increase the production of nitric oxide by the endothelial cells through the ETB receptor (8). In the kidney, ETB is expressed at ~10 times the level of ETA throughout the tubule epithelium (6, 31, 49, 50). Our data suggest that enalapril may ameliorate the pathology of the obstructed kidney by increasing the level of nitric oxide not only through the kinin-bradykinin system but also by upregulation of the ETB receptor. Interestingly, Wong et al. (53) reported the downregulation of ETB in cardiomyopathic hamsters and showed that enalapril therapy restored ETB receptor density in these animals. In another study, renal injury was exacerbated in rats genetically deficient in the ETB receptor compared with normal rats in a deoxycorticosterone-salt hypertension model (38). Furthermore, Forbes et al. (13) have shown that a dual ETA-ETB antagonist exacerbated long-term abnormalities in renal function consequent to an ischemic episode. This suggests that the ETB has an overall beneficial effect on renal pathophysiological processes. In some experimental models of renal disease, ETB expression is increased (35, 42, 55). In a previous study of a rabbit model of partial bladder outlet obstruction, there was a downregulation of ETB receptors in the medulla (24). This was measured 6 wk after partial bladder obstruction, whereas our study focuses on the renal cortex and more acute effects of obstructive nephropathy. Our study points to a beneficial effect of the ETB receptor on the expansion of interstitium as blockade with BQ-788 partially but significantly reversed the effects of enalapril. Additional studies measuring nitric oxide production and blockade of the bradykinin B2 receptor would help to fully elucidate the beneficial mechanisms of ACE inhibition.
In the present study in the kidney with an obstructed ureter, enalapril
ameliorated the mRNA expression of TGF- and TNF-
major cytokines
in the regulation of ECM proteins. Morphometric analysis also showed
that enalapril treatment significantly suppressed the expansion of the
interstitium in the obstructed kidney. These results are consistent
with our previous data in rats and mice (19-21). The
dose of enalapril might need to be tailored for the model of renal
disease, because Ikoma et al. (17) showed the greater
effect with low dose (50 mg/l) than high dose (200 mg/l). Ikoma et al.
focused on glomerular fibrosis, whereas our laboratory has focused on
tubulointerstitial fibrosis (19-23).
Administration of enalapril did not decrease TNF- mRNA levels on a
percent basis in the kidney with an obstructed ureter as much as it
decreased TGF-
mRNA. This is consistent with previous observations
of the rats (10) and mice (29) in which
enalapril treatment succeeded in blunting TNF-
mRNA expression but
not to the extent seen for TGF-
. Angiotensin II appears to
contribute to the early phase of increase in TNF-
mRNA expression in
the obstructed kidney (10). The source of TNF-
synthesis may be different according to the time after the obstruction
and level of ACE inhibition.
Again, using mice with UUO, we have shown the beneficial effects of
enalapril on the progression of interstitial fibrosis and expansion due
to the unilateral ureteral ligation. This is a well-established
observation. Enalapril administration blunted the increased mRNA
expression TGF- and to a great degree ameliorated the histological
appearance of tubulointerstitial fibrosis in the obstructed kidney of
mice with UUO. However, the level of TGF-
mRNA and the histological
change in the obstructed kidney did not return completely to the
control level even when treated with enalapril. These results strongly
suggest the existence of other factors besides angiotensin II that are
involved in the progression of interstitial fibrosis in this setting or
the escape of some pathophysiological factor to ACE inhibition. The
present results point to endothelin expression as being a factor, in
part, in renal fibrosis.
In summary, we have shown that enalapril significantly but incompletely blunts the increased expression of ET-1 mRNA in the obstructed kidney from UUO mice at 5 days after the onset of obstruction. To evaluate the direct interaction between ET-1 and tubulointerstitial fibrosis in the UUO model, however, experiments using selective ETA and ETB receptor blockers would be necessary. On the contrary, enalapril increased the mRNA expression of ETB receptor in the obstructed kidney. These data may be very important because ET-1 can promote nitric oxide production by endothelial cells through ETB and implicates another potential mechanism by which ACE inhibitors exert a beneficial effect on renal disease apart from lowering angiotensin II formation. A moderate amount of nitric oxide is beneficial to prevent and alleviate tubulointerstitial fibrosis. It may be worthwhile exploring the role of ETB in the kidney with an obstructed ureter for more details and its interaction among the renin-angiotensin, kinin-bradykinin, and nitric oxide systems.
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ACKNOWLEDGEMENTS |
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The assistance of Monica Waller in the preparation of this manuscript is acknowledged.
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FOOTNOTES |
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This work is 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), MS 90-32-648, 216 S. Kingshighway Blvd., St. Louis, MO 63110-1092 (E-mail:morrisse{at}im.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.
10.1152/ajprenal.00352.2001
Received 27 November 2001; accepted in final form 28 August 2002.
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