Department of Pediatrics, University of Virginia, School of Medicine, Charlottesville, Virginia 22908
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Renal angiotensin II (ANG II) is increased as a result of
unilateral ureteral obstruction (UUO), and angiotensin
AT2 receptors predominate over
AT1 receptors in the early
postnatal period. To examine the renal cellular response to 3-day UUO
in the neonatal and adult rat, AT1
and AT2 receptors were inhibited
by losartan and PD-123319, respectively. Additional rats received
exogenous ANG II, 0.5 mg · kg1 · day
1.
Renal cellular proliferation and apoptosis were quantitated by
proliferating cell nuclear antigen and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling
technique, respectively. In the neonate, UUO reduced
proliferation and increased tubular apoptosis. Losartan had no
detectable cellular effect, whereas PD-123319 increased cellular
proliferation and suppressed apoptosis, and exogenous ANG II stimulated
apoptosis. In the adult, UUO increased cellular proliferation as well
as apoptosis, whereas losartan, PD-123319, and exogenous ANG II did not
alter the cellular response. In conclusion, UUO impairs renal growth in
the neonate by reducing proliferation and stimulating apoptosis, at
least in part through angiotensin
AT2 receptors. UUO stimulates both renal cellular proliferation and apoptosis in the adult, but these effects are independent of ANG II. We speculate that the unique early
responses of the developing kidney to urinary tract obstruction are
mediated by a highly activated renin-angiotensin system and preponderance of AT2 receptors.
rat; hydronephrosis; development; AT2 receptor
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
OBSTRUCTIVE NEPHROPATHY is a significant cause of renal insufficiency in neonates and adults. We have shown that unilateral ureteral obstruction (UUO) in the neonatal rat impairs renal growth and development, whereas UUO in the adult induces a marked interstitial infiltrate that is significantly greater than in the neonate (1). In the neonate, chronic UUO impairs cellular proliferation and reduces the renal DNA content, whereas in the adult, UUO stimulates renal cell proliferation and increases renal DNA content (1). Moreover, although UUO induces renal cellular apoptosis in both neonates and adults, the magnitude of apoptosis is significantly greater in the neonate (1). We have demonstrated also that chronic UUO in the neonatal rat markedly stimulates the renin-angiotensin system (RAS), with a persistent increase in renin secretion and intrarenal angiotensin II (ANG II) production (20, 33). The stimulation of renin expression is greater in the neonate than in the adult rat (1).
The AT1 receptor is known to mediate the vasoconstrictor action of ANG II, as well as many of its growth-promoting actions (30). Expression of this receptor in the kidney increases progressively throughout postnatal life, whereas expression of the AT2 angiotensin receptor is greatest in the fetal and perinatal period, with a progressive decrease after birth (9, 33). The function of the AT2 receptor is less well understood than that of the AT1 receptor, but it appears to mediate the inhibition of cellular proliferation (17, 27) and the stimulation of apoptosis (29, 32). We have shown previously that UUO in the neonatal rat modulates the expression of ANG II receptors: expression of both AT1 and AT2 renal receptors is downregulated within the first 24 h of obstruction, whereas AT2 receptor expression decreases in the first 3-14 days of postnatal life regardless of UUO (33). However, as a result of prolonged UUO, renal AT1 receptor expression increases progressively, concurrent with an elevation in renal ANG II content (33).
In the present study, we hypothesized that ANG II mediates the early renal cellular response to UUO and that this response is determined by the relative abundance of AT1 and AT2 receptors. We further hypothesized that the greater expression of AT2 receptors in the neonate mediates the enhanced apoptosis and reduced proliferation in the neonatal compared with the adult rat kidney subjected to chronic UUO. The present study was therefore designed to compare the role of ANG II AT1 and AT2 receptors in the early renal cellular responses to UUO in neonatal and adult rats. Since the abundance of AT2 receptors exceeds that of AT1 receptors in the first several days of life, the studies were performed 3 days following UUO in neonatal rats, then compared with similarly treated adult rats. Immunohistochemistry and morphometry were used to measure glomerular maturation, as well as renal tubular and interstitial cellular proliferation and apoptosis in the obstructed and the intact opposite kidneys. The contribution of AT1 and AT2 receptors was examined using selective receptor blockers administered chronically throughout the period of study. To evaluate the renal response to ANG II, exogenous ANG II was infused chronically in additional groups of animals.
![]() |
METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Experimental protocol. Experiments were performed using 82 neonatal and 95 adult Sprague-Dawley rats. Animals were anesthetized with halothane and oxygen and subjected to UUO as described previously (7). Briefly, the left ureter was exposed through an abdominal incision, ligated, and the incision was closed. Neonatal animals were returned to their mothers, whereas adult animals were returned to their cages following recovery.
As shown in Fig. 1, animals in each age
range were divided into six groups and treated with either saline
vehicle injection, losartan, PD-123319, ANG II, ANG II plus losartan,
or ANG II plus PD-123319. Losartan (gift of Merck, Rahway, NJ), a
selective ANG II AT1 receptor
blocker, was administered at 40 mg · kg1 · day
1
via daily subcutaneous injections. This dose of losartan was chosen
because it effectively blocks the vasoconstrictor response to ANG II,
and no toxic effects were observed in rats receiving 45 mg · kg
1 · day
1
over 1-3 mo (31). PD-123319 (gift of Parke-Davis, Ann Arbor, MI),
a selective AT2 receptor
inhibitor, was administered from timed-released pellets (Innovative
Research of America, Sarasota, FL) placed intraperitoneally at the time
of ureteral obstruction. Use of pellets, rather than osmotic minipumps,
was necessary in neonatal rats due to the small size of the animals.
The pellets have been shown to release compounds reliably in a number
of studies (8, 18, 26), and were designed to release PD-123319 at a
rate of 10 mg · kg
1 · day
1.
This dose was selected because administration of 3 mg · kg
1 · day
1
in the rat inhibits DNA synthesis following myocardial infarction (12),
and 30 mg · kg
1 · day
1
antagonizes ANG II-induced aortic hypertrophy and fibrosis (14). ANG II
was administered also via timed-release pellets, releasing 0.5 mg · kg
1 · day
1,
a nonhypertensive dose (34). Control animals were injected daily with
normal saline vehicle, whereas animals not receiving PD-123319 or ANG
II were given placebo timed-release pellets such that every animal had
the same number of injections and pellets.
|
In adult rats, losartan, PD-123319, and ANG II were administered in the same doses as in the neonatal animals (factored for body weight). Losartan was administered through daily subcutaneous injections, whereas PD-123319 and ANG II were administered using osmotic minipumps (models 1003D and 2001; Alzet Pharmaceuticals, Palo Alto, CA). Control animals were injected daily with saline vehicle and received osmotic minipumps containing bovine serum albumin (vehicle). The distribution of rats in experimental groups is shown in Fig. 1.
Seventy-two hours after UUO, rats were killed by lethal dose of intraperitoneal pentobarbital sodium. Both kidneys were removed, decapsulated, weighed, and fixed in 10% buffered Formalin following dehydration through graded alcohols and xylene, then embedded in paraffin for sectioning at 4 µm.
Glomerular maturation. Late glomerular maturation was scored in 10 nonoverlapping fields spanning the renal cortex of midcoronal sections stained using the periodic acid-Schiff technique. Glomerular maturation and calculation of the weighted glomerular maturation index were determined as published previously (19).
Determination of cellular
proliferation. Proliferating nuclei were identified in
sections by proliferating cell nuclear antigen (PCNA, 1:400; Vector
Laboratories, Burlingame, CA) using the method described previously
(2). Sections were counterstained in Gill's hematoxylin, dehydrated
through graded alcohols and xylene, and mounted. Nuclei appeared as
dark brown staining and were present in tubules and interstitium (Fig.
2A).
|
Determination of apoptosis. Apoptosis was quantitated using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) technique (Apoptag; Oncor, Gaithersburg, MD) as described previously (2). Slides were counterstained in Gill's hematoxylin, dehydrated through alcohol and xylene, and mounted. In addition to brown staining, apoptotic nuclei were identified by condensed nuclear material and vacuolization of the cytoplasm (Fig. 2B).
Both tubular and interstitial proliferating and apoptotic cells were quantitated by counting the number of positively stained nuclei in 10 nonoverlapping fields viewed at ×450 magnification. Care was taken to distribute the fields across cortex and medulla of both poles and the center of each kidney. There was no detectable variation in the density of PCNA or TUNEL-positive cells between fields in an individual kidney.
Statistical analysis. The effects of AT1 and AT2 receptor inhibitor and of exogenous ANG II were analyzed using two-way ANOVA with Tukey pairwise multiple comparison. Differences between obstructed and intact opposite kidneys were determined using Student's t-test for paired data. Statistical significance was defined as being less than 0.05. Data are expressed as means ± SE.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
As shown in Table 1, there was no
significant effect of angiotensin receptor antagonists or ANG II
infusion on body weight in neonatal or adult rats. As shown in Table
2, UUO resulted in an increase in kidney
weight-to-body weight ratio in both neonatal and adult groups. Weight
of the obstructed and intact opposite kidneys in neonates was reduced
by losartan (P < 0.01 by 2-way ANOVA). Administration of ANG II increased the weight of the obstructed kidney (P < 0.02 by 2-way ANOVA) but
not of the intact opposite kidney. There was no effect of ANG II or of
angiotensin receptor inhibition on kidney weight in adult rats. As
shown in Table 3, there was a reduction in
the glomerular maturation index in the cortex of the obstructed
compared with the intact opposite kidney (P < 0.001 by 2-way ANOVA). There
was no effect of angiotensin receptor inhibition or of ANG II infusion
on glomerular maturation of the left or right kidney of any of the
groups.
|
|
|
As shown in Fig.
3A,
compared with the intact opposite kidney, UUO reduced renal tubular
cell proliferation in the neonate. There was a tendency for losartan to
reduce further tubular cell proliferation, but this was not
significant. However, infusion of PD-123319 doubled renal tubular cell
proliferation in both obstructed and intact opposite kidneys
(P < 0.05). Administration of
exogenous ANG II had no significant additional effects on tubular cell
proliferation.
|
As shown in Fig. 3B, tubular cell apoptosis was markedly increased in the obstructed compared with the intact opposite kidney in all groups of neonatal rats. Administration of losartan tended to decrease tubular apoptosis, but this was not statistically significant. However, administration of PD-123319 significantly decreased apoptosis in the obstructed kidney by ~50%, whereas infusion of exogenous ANG II significantly enhanced apoptosis in the obstructed kidney.
As shown in Fig. 3C, interstitial cell proliferation was unaffected by UUO in neonatal rats, but increased more than twofold in the intact kidney as a result of inhibition of AT2 receptors. There was no significant effect of exogenous ANG II on interstitial cell proliferation.
As shown in Fig. 3D, renal interstitial cell apoptosis was undetectable in the intact kidney but increased in the obstructed kidney of neonatal rats. There was a further increase in interstitial cell apoptosis in the obstructed kidney as a result of ANG II infusion, but no significant effect of inhibition of either AT1 or AT2 receptors.
As shown in Fig.
4A, UUO
had the opposite effect on renal tubular cell proliferation in the
adult compared with the neonatal rat: there was a consistent increase
in tubular cell proliferation in the obstructed kidney, although the
overall prevalence of tubular cell proliferation was less than in the
neonate (P < 0.05). There was no
effect of AT1 or
AT2 inhibition or exogenous ANG II
infusion on renal tubular cell proliferation in either the obstructed
or the intact opposite kidneys.
|
As shown in Fig. 4B, there was a significant increase in renal tubular cell apoptosis as a result of ureteral obstruction, although the magnitude of apoptosis was lower in the adult than the neonate (P < 0.05). As with tubular cell proliferation, there was no modulation of this effect as the result of either AT1 or AT2 receptor inhibition or of ANG II infusion.
As shown in Fig. 4C, compared with the intact opposite kidney, UUO resulted in a consistent increase in renal interstitial cell proliferation, a response not observed in the neonate. There was no additional effect of AT1 or AT2 inhibition or of ANG II infusion on renal interstitial cell proliferation in adult rats.
As shown in Fig. 4D, UUO induced a significant increase in renal interstitial cell apoptosis compared with the intact opposite kidney. Unlike the neonate, in which apoptosis was greater in tubules than interstitium, in the adult, the prevalence of apoptotic interstitial nuclei was similar to that of tubular nuclei. There was no effect of AT1 or AT2 receptor inhibition or of ANG II infusion on renal interstitial cell apoptosis in either kidney.
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The major findings in this study highlight the importance of the RAS in modulating the early renal cellular response to chronic urinary tract obstruction in the neonate, but not the adult. Acting via AT2 receptors, ANG II significantly inhibited cellular proliferation and stimulated apoptosis in renal tubules of the obstructed neonatal rat kidney: exogenous ANG II further aggravated tubular apoptosis. Although we demonstrated a transient reduction in renal AT1 and AT2 receptor binding 24 h following ipsilateral UUO in the neonatal rat, receptor binding was not different from the intact opposite kidney after 3-day obstruction (33). The relative abundance of renal mRNA for AT2 receptor is 10-fold greater than that of AT1 receptor at 1 day of age, approximately equal at 7 days of age, and over 30-fold less than AT1 at 14 days (16). Since we have shown that renal AT1 and AT2 receptor binding parallels steady-state mRNA content (33), it is likely that the dramatic effects of AT2 receptor inhibition on renal cell proliferation and apoptosis in the neonate are due to a preponderance of this class of receptors coupled with the marked activation of the RAS in the perinatal period (10). Renal renin mRNA is significantly greater in the obstructed kidney than in the intact opposite or sham-operated kidney 3, 7, 14, and 28 days following UUO in the neonatal rat (6, 33). Moreover, compared with its normal juxtaglomerular localization, immunoreactive renin extends along the length of the afferent arteriole following 5 days of UUO in the neonatal rat (3). These findings indicate an early and persistent activation of the RAS following neonatal UUO. Increased generation of endogenous ANG II would therefore likely contribute to the renal tubular cellular changes of the present study.
Immunohistochemical studies have shown that AT2 receptors are present in vessels, glomeruli, and tubules of the 19-day fetal and neonatal rat kidney (21). Others have demonstrated that activation of the AT2 receptor leads to dephosphorylation of Bcl-2, an oncoprotein that inhibits apoptosis (11). This is consistent with our observation that chronic UUO reduces Bcl-2 expression in dilated apoptotic tubules of the obstructed kidney (4). An alternate angiotensin-dependent stimulus for apoptosis through reduction in Bcl-2 may be triggered by renal tubular stretch and mediated by the AT1 receptors under the stimulus of p53 (13, 23). The renal distribution of AT1 receptors is similar to that of AT2 receptors, with preponderance in the microvasculature and proximal tubules (22).
Although all components of the renal RAS are activated immediately following UUO in the adult (24, 25), the lack of effects of inhibition of AT1 and AT2 receptors on cellular proliferation and apoptosis in the adult rats of the present study likely reflects the overwhelming preponderance of AT1 over AT2 receptors, as well as the attenuated cellular dynamics of the mature kidney compared with the developing kidney. Other factors are therefore responsible for the stimulation of tubular proliferation and apoptosis by UUO in the adult kidney.
Although we found a consistent increase in weight of the obstructed compared with the intact contralateral kidney in both neonates and adults, this is presumably due to accumulation of edema in the early phase of obstruction. This is consistent with our previous report showing an increase in the weight of the obstructed neonatal rat kidney 1 and 3 days following UUO (6). Although changes in DNA content of the obstructed kidney are not detectable within the first week of obstruction (6), we have also shown previously that with prolonged UUO (14 days), the DNA content of the obstructed kidney is reduced in the neonate but augmented in the adult (1). This is consistent with a predominant AT2-mediated antiproliferative effect of endogenous ANG II in the neonate, compared with a predominantly proliferative response to AT1 stimulation in the adult. Our finding that losartan reduced wet kidney weight while ANG II increased kidney weight in the neonate is likely due to suppression and stimulation of AT1-mediated sodium retention demonstrated previously in the neonatal rat (5).
Whereas 3-day UUO delayed maturation of the neonatal kidney, administration of ANG II did not alter maturation. Others have shown that glomerular maturation is delayed in mice homozygous for a null mutation in the angiotensinogen gene, although the effect was not found to be statistically significant until 1 wk of age (19). It is likely that the preponderance of AT2 receptors prior to 1 wk of age serves to limit the proliferative action of ANG II, whereas the rapid dominance of the AT1 receptors after that time accounts for the trophic effect of ANG II on later glomerular maturation.
In a recent report, adult mice with a null mutation of the AT2 receptor gene were subjected to chronic UUO (15). Although cellular proliferation was not different in the mutant mouse obstructed kidneys, there were more interstitial fibroblasts as well as greater interstitial collagen deposition in the mutants (15). This may be explained at least in part by increased intrarenal angiotensin-converting enzyme activity in the mutant hydronephrotic kidneys (28), which would enhance stimulation of fibrogenic cytokines through activation of AT1 receptors, as well as deplete antiproliferative factors such as bradykinin or nitric oxide. Thus, whereas loss of tubular cells contributes to tubular atrophy, depletion of interstitial cells may be beneficial with respect to progression of interstitial fibrosis.
In summary, UUO in the neonatal rat suppresses cellular proliferation and induces apoptosis in tubules of the ipsilateral kidney. These effects are modulated by ANG II primarily through stimulation of the AT2 receptor. In the adult, UUO stimulates both proliferation and apoptosis in the obstructed kidney, events which are mediated by factors other than ANG II. It is likely that the increased activity of the RAS and preponderance of AT2 over AT1 receptors in the neonatal kidney contribute to the greater renal damage in the developing kidney consequent to chronic urinary tract obstruction.
![]() |
ACKNOWLEDGEMENTS |
---|
This research was supported in part by National Institutes of Health (NIH) Research Center of Excellence in Pediatric Nephrology and Urology Grants DK-44756 and DK-52612, NIH O'Brien Center of Excellence in Nephrology and Urology Grant DK-45179, and NIH Child Health Research Center Grant HD-28810.
![]() |
FOOTNOTES |
---|
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 reprint requests and other correspondence: R. L. Chevalier, Dept. of Pediatrics, Box 386, Univ. of Virginia, Health Sciences Center, Charlottesville, VA 22908 (E-mail: rlc2m{at}virginia.edu).
Received 10 December 1998; accepted in final form 18 March 1999.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Chevalier, R. L.,
K. H. Chung,
C. D. Smith,
M. Ficenec,
and
R. A. Gomez.
Renal apoptosis and clusterin following ureteral obstruction: the role of maturation.
J. Urol.
156:
1474-1479,
1996[Medline].
2.
Chevalier, R. L.,
S. Goyal,
J. T. Wolstenholme,
and
B. A. Thornhill.
Obstructive nephropathy in the neonate is attenuated by epidermal growth factor.
Kidney Int.
54:
38-47,
1998[Medline].
3.
Chevalier, R. L.,
A. Kim,
B. A. Thornhill,
and
J. T. Wolstenholme.
Recovery following relief of unilateral ureteral obstruction in the neonatal rat.
Kidney Int.
55:
793-807,
1999[Medline].
4.
Chevalier, R. L., C. D. Smith, J. T. Wolstenholme, S. Krajewski, and J. C. Reed. Chronic
ureteral obstruction in the rat suppresses renal tubular bcl-2 and
stimulates apoptosis. Exp. Nephrol. In press.
5.
Chevalier, R. L.,
B. A. Thornhill,
D. C. Belmonte,
and
A. J. Baertschi.
Endogenous angiotensin II inhibits natriuresis following acute volume expansion in the neonatal rat.
Am. J. Physiol.
270 (Regulatory Integrative Comp. Physiol. 39):
R393-R397,
1996
6.
Chung, K. H.,
and
R. L. Chevalier.
Arrested development of the neonatal kidney following chronic ureteral obstruction.
J. Urol.
155:
1139-1144,
1996[Medline].
7.
Chung, K. H.,
R. A. Gomez,
and
R. L. Chevalier.
Regulation of renal growth factors and clusterin by angiotensin AT1 receptors during neonatal ureteral obstruction.
Am. J. Physiol.
268 (Renal Fluid Electrolyte Physiol. 37):
F1117-F1123,
1995
8.
Davidson, J. M.,
and
K. N. Broadley.
Manipulation of the wound-healing process with basic fibroblast growth factor.
Ann. NY Acad. Sci.
638:
306,
1991[Medline].
9.
Gomez, R. A.
Angiotensin receptors: relevance in development and disease states.
Exp. Nephrol.
2:
259-268,
1994[Medline].
10.
Gomez, R. A.,
and
V. F. Norwood.
Developmental consequences of the renin-angiotensin system.
Am. J. Kidney Dis.
26:
409-431,
1995[Medline].
11.
Horiuchi, M.,
W. Hayashida,
T. Kambe,
T. Yamada,
and
V. J. Dzau.
Angiotensin type 2 receptor dephosphorylates Bcl-2 by activating mitogen-activated protein kinase phosphatase-1 and induces apoptosis.
J. Biol. Chem.
272:
19022-19026,
1997
12.
Kuizinga, M. C.,
J. M. Smits,
J. W. Arends,
and
M. P. Daemen.
AT2 receptor blockade reduces cardiac interstitial cell DNA synthesis and cardiac function after rat myocardial infarction.
J. Mol. Cell. Cardiol.
30:
425-434,
1998[Medline].
13.
Leri, A.,
P. P. Claudio,
Q. Li,
X. W. Wang,
K. Reiss,
S. G. Wang,
A. Malhotra,
J. Kajstura,
and
P. Anversa.
Stretch-mediated release of angiotensin II induces myocyte apoptosis by activating p53 that enhances the local renin-angiotensin system and decreases the Bcl-2-to-Bax protein ratio in the cell.
J. Clin. Invest.
101:
1326-1342,
1998
14.
Levy, B. I.,
J. Benessiano,
D. Henrion,
L. Caputo,
C. Heymes,
M. Duriez,
P. Poitevin,
and
J. L. Samuel.
Chronic blockade of AT2-subtype receptors prevents the effect of angiotensin II on the rat vascular structure.
J. Clin. Invest.
98:
418-425,
1996
15.
Ma, J.,
H. Nishimura,
A. Fogo,
V. Kon,
T. Inagami,
and
I. Ichikawa.
Accelerated fibrosis and collagen deposition develop in the renal interstitium of angiotensin type 2 receptor null mutant mice during ureteral obstruction.
Kidney Int.
53:
937-944,
1998[Medline].
16.
Mauch, T. J.,
G. Yang,
E. Howe,
K. M. Baker,
and
D. E. Dostal.
Determination of renin-angiotensin system component mRNA levels in developing rat kidney using multiplex polymerase chain reaction (Abstract).
J. Am. Soc. Nephrol.
8:
363,
1997.
17.
Nakajima, M.,
H. G. Hutchinson,
M. Fujinaga,
W. Hayashida,
R. Morishita,
L. Zhang,
M. Horiuchi,
R. E. Pratt,
and
V. J. Dzau.
The angiotensin II type 2 (AT2) receptor antagonizes the growth effects of the AT1 receptor: gain-of-function study using gene transfer.
Proc. Natl. Acad. Sci. USA
92:
10663-10667,
1995[Abstract].
18.
Nelson, K. G.,
T. Takahashi,
N. L. Bossert,
D. K. Walmer,
and
J. A. McLachlan.
Epidermal growth factor replaces estrogen in the stimulation of female genital-tract growth and differentiation.
Proc. Natl. Acad. Sci. USA
88:
21-25,
1991[Abstract].
19.
Niimura, F.,
P. A. Labosky,
J. Kakuchi,
S. Okubo,
H. Yoshida,
T. Oikawa,
T. Ichiki,
A. J. Naftilan,
A. Fogo,
T. Inagami,
B. L. M. Hogan,
and
I. Ichikawa.
Gene targeting in mice reveals a requirement for angiotensin in the development and maintenance of kidney morphology and growth factor regulation.
J. Clin. Invest.
96:
2947-2954,
1995[Medline].
20.
Norwood, V. F.,
R. M. Carey,
K. M. Geary,
P. A. Jose,
R. A. Gomez,
and
R. L. Chevalier.
Neonatal ureteral obstruction stimulates recruitment of renin- secreting renal cortical cells.
Kidney Int.
45:
1333-1339,
1994[Medline].
21.
Ozono, R.,
Z. Q. Wang,
A. F. Moore,
T. Inagami,
H. M. Siragy,
and
R. M. Carey.
Expression of the subtype 2 angiotensin (AT2) receptor protein in rat kidney.
Hypertension
30:
1238-1246,
1997
22.
Paxton, W. G.,
M. Runge,
C. Horaist,
C. Cohen,
R. W. Alexander,
and
K. E. Bernstein.
Immunohistochemical localization of rat angiotensin II AT1 receptor.
Am. J. Physiol.
264 (Renal Fluid Electrolyte Physiol. 33):
F989-F995,
1993
23.
Pierzchalski, P.,
K. Reiss,
W. Cheng,
C. Cirielli,
J. Kajstura,
J. A. Nitahara,
M. Rizk,
M. C. Capogrossi,
and
P. Anversa.
p53 induces myocyte apoptosis via the activation of the renin-angiotensin system.
Exp. Cell Res.
234:
57-65,
1997[Medline].
24.
Pimentel, J. L., Jr.,
M. Martinez-Maldonado,
J. N. Wilcox,
S. Wang,
and
C. Luo.
Regulation of renin-angiotensin system in unilateral ureteral obstruction.
Kidney Int.
44:
390-400,
1993[Medline].
25.
Pimentel, J. L., Jr.,
A. Montero,
S. S. Wang,
I. Yosipiv,
S. El-Dahr,
and
M. Martinez-Maldonado.
Sequential changes in renal expression of renin-angiotensin system genes in acute unilateral ureteral obstruction.
Kidney Int.
48:
1247-1253,
1995[Medline].
26.
Stagner, J. I.,
and
E. Samois.
The induction of capillary bed development by endothelial cell growth factor before islet transplantation may prevent islet ischemia.
Transplant. Proc.
22:
824-828,
1990[Medline].
27.
Stoll, M.,
U. M. Steckelings,
M. Paul,
S. P. Bottari,
R. Metzger,
and
T. Unger.
The angiotensin AT2-receptor mediates inhibition of cell proliferation in coronary endothelial cells.
J. Clin. Invest.
95:
651-657,
1995[Medline].
28.
Stoneking, B. J.,
T. E. Hunley,
H. Nishimura,
J. Ma,
A. Fogo,
T. Inagami,
M. Tamura,
M. C. Adams,
J. W. Brock III,
and
V. Kon.
Renal angiotensin converting enzyme promotes renal damage during ureteral obstruction.
J. Urol.
160:
1070-1074,
1998[Medline].
29.
Tanaka, M.,
J. Ohnishi,
Y. Ozawa,
M. Sugimoto,
S. Usuki,
M. Naruse,
K. Murakami,
and
H. Miyazaki.
Characterization of angiotensin II receptor type 2 during differentiation and apoptosis of rat ovarian cultured granulosa cells.
Biochem. Biophys. Res. Commun.
207:
593-598,
1995[Medline].
30.
Wolf, G.
Regulation of renal tubular cell growth: effects of angiotensin II.
Exp. Nephrol.
2:
107-114,
1994[Medline].
31.
Wong, P. C.,
T. B. Barnes,
A. T. Chiu,
D. D. Christ,
J. V. Duncia,
W. F. Herblin,
and
P. B. M. W. M. Timmermans.
Losartan (DuP 753), an orally active nonpeptide angiotensin II receptor antagonist.
Cardiovasc. Drugs Ther.
9:
317-339,
1991.
32.
Yamada, T.,
M. Horiuchi,
and
V. J. Dzau.
Angiotensin II type 2 receptor mediates programmed cell death.
Proc. Natl. Acad. Sci. USA
93:
156-160,
1996
33.
Yoo, K. H.,
V. F. Norwood,
S. S. El-Dahr,
I. Yosipiv,
and
R. L. Chevalier.
Regulation of angiotensin II AT1 and AT2 receptors in neonatal ureteral obstruction.
Am. J. Physiol.
273 (Regulatory Integrative Comp. Physiol. 42):
R503-R509,
1997
34.
Yoo, K. H.,
B. A. Thornhill,
J. T. Wolstenholme,
and
R. L. Chevalier.
Tissue-specific regulation of growth factors and clusterin by angiotensin II.
Am. J. Hypertens.
11:
715-722,
1998[Medline].