(Hypertension. 1999;33:732-739.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Angiotensin-Converting Enzyme Is Upregulated in the Proximal Tubules of Rats With Intense Proteinuria
From the Renal and Vascular Research Laboratory, Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain.
Correspondence to Jesús Egido, MD, PhD, Servicio de Nefrología, Fundación Jiménez Díaz, Avda Reyes Católicos 2, 28040 Madrid, Spain. E-mail ehiper{at}uni.fjd.es
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Abstract |
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Abstract—Persistent proteinuria is considered a deleterious prognostic factor in most progressive renal diseases. However, the mechanisms by which proteinuria induces renal damage remain undetermined. Since proximal tubular cells possess all the machinery to generate angiotensin II (Ang II), we approached the hypothesis that proteinuria could elicit the renal activation of the renin-angiotensin system in a model of intense proteinuria and interstitial nephritis induced by protein overload. After uninephrectomy (UNX), Wistar-Kyoto rats received daily injections of 1 g BSA or saline for 8 days. The mean peak of proteinuria was observed at the fourth day (538±89 versus 3±1 mg/24 h in UNX controls; n=12; P<0.05) and was increased during the whole study period (at the eighth day: 438±49 mg/24 h; n=12; P=NS). Morphological examination of the kidneys at the end of the study showed marked tubular lesions (atrophy, vacuolization, dilation, and casts), interstitial infiltration of mononuclear cells, and mesangial expansion. In relation to UNX control rats, renal cortex of BSA-overloaded rats showed an increment in the gene expression of angiotensinogen (2.4-fold) and angiotensin-converting enzyme (ACE) (2.1-fold), as well as a diminution in renin gene expression. No changes were observed in angiotensin type 1 (AT1) receptor mRNA expression in both groups of rats. By in situ reverse transcription–polymerase chain reaction and immunohistochemistry, ACE expression (gene and protein) was mainly localized in proximal and distal tubules and in the glomeruli. By immunohistochemistry, angiotensinogen was localized only in proximal tubules, and AT1 receptor was localized mainly in proximal and distal tubules. In the tubular brush border, an increase in ACE activity was also seen (5.5±0.5 versus 3.1±0.7 U/mg protein x10-4 in UNX control; n=7; P<0.05). Our results show that in the kidney of rats with intense proteinuria, ACE and angiotensinogen were upregulated, while gene expression of renin was inhibited and AT1 was unmodified. On the whole, these data suggest an increase in Ang II intrarenal generation. Since Ang II can elicit renal cell growth and matrix production through the activation of AT1 receptor, this peptide may be responsible for the tubulointerstitial lesions occurring in this model. These results suggest a novel mechanism by which proteinuria may participate in the progression of renal diseases.
Key Words: renin-angiotensin system • proteinuria • cells, tubular epithelial • interstitial damage
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Introduction |
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Progressive renal diseases are characterized by an interstitial infiltrate of mononuclear cells and the gradual destruction of the tubulointerstitial structure. It has been shown that there is a better correlation of renal function and disease progression with interstitial than with glomerular lesions.1 The factors that cause the progression of intrinsic renal disease to end-stage renal failure are ill defined and poorly understood. However, persistent proteinuria is always considered an aggravating factor.1 2 In addition, in both human and experimental renal diseases, the degree of proteinuria is well correlated with the rate of progression of renal failure.2 Indeed, maneuvers that result in a reduction in the severity of proteinuria retard the development of progressive renal impairment.1 2
The mechanisms by which proteinuria per se is associated with interstitial inflammation and fibrosis are unknown. Proximal tubular cells reabsorb proteins present in the tubular fluid and are thus vulnerable to the excessive and prolonged traffic of proteins.3 Recent evidence suggests that tubular protein overload upregulates and/or activates proinflammatory and vasoactive genes such as monocyte chemoattractant protein-1 (MCP-1), RANTES (regulated on activation, normal T cell expressed and secreted), and endothelin-1 (ET-1).1 3
The renin-angiotensin system (RAS) has been implicated in the progression of renal damage. Angiotensin-converting enzyme (ACE) inhibition reduces proteinuria and limits progressive deterioration of renal function in a great variety of renal diseases, independently of the presence of hypertension.1 4 5 However, the role of the RAS in the pathogenesis of tubulointerstitial lesion is not completely understood.
Since proximal tubular cells possess all the machinery to generate angiotensin II (Ang II),6 the main objective of this study was to establish whether proteinuria could activate some of the components of the RAS (ACE, angiotensinogen, renin, and angiotensin type 1 [AT1] receptor) in the kidney of rats with tubulointerstitial injury caused by protein overload. This nephritis is characterized by an early and impressive interstitial inflammation, and it has been proved that it is a valuable model to investigate the relationship between proteinuria and renal damage.7
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Methods |
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Animal Model
Female Wistar-Kyoto rats (100 to 150 g) were fed standard rat chow ad libitum and given free access to water. Uninephrectomized (UNX) rats received daily injections of 1 g of BSA (Sigma) or saline for 8 days, as described.8 Periodically, 24-hour urine was collected for protein measurement by the sulfosalicylic acid method. At the end of the study, animals were anesthetized with pentobarbital sodium (5 mg/100 g body wt). Blood was collected, and kidneys were perfused with cold sodium saline and removed.
Renal Histopathological Studies
For light microscopy, paraffin-embedded sections (4 µm
thick) were prepared and stained with hematoxylin-eosin and Masson's
trichrome. For each animal, renal damage was graded from 0 to 4 by a
semiquantitative score previously reported.8 All these
studies were performed by 2 observers in a blinded fashion.
RNA Extraction and Reverse Transcription and Polymerase Chain
Reaction
Pieces of renal cortex were homogenized, and total
RNA was obtained by the acid guanidinium-phenol-chloroform
method.9 Isolated RNA was reverse transcribed and then
amplified with a commercial kit (Access RT-PCR System, Promega),
with the use of specific primers for rat
angiotensinogen (sense: 5'-TTCAGGCCAAGACCTCCC-3';
antisense: 5'-CCAGCCGGGAGGTGCAGT-3'; fragment: 308 base pair
length), renin (sense: 5'-CGGTGGTCCTCACCAACT-3'; antisense:
5'-GCCCATGCCCAGACCCCC-3'; fragment: 368 base pair length), ACE
(sense: 5'-CCTGATCAACCAGGAGTTTGCAGAG-3'; antisense:
5'-GCCAGCCTTCCCAGGCAAACAGCAC-3'; fragment: 317 base pair length), and
AT1 (sense: 5'-TGGAAACAGCTTGGTGGTGAT-3';
antisense: 5'-GCACAATCGCCATAATTATCC-3'; fragment: 607 base pair
length) (a sequence with no divergence between
AT1a and AT1b receptors)
that were designed according to the published
sequences.10 11 12 13 We performed RT-PCR of GAPDH as internal
standard.14 The optimum number of amplification cycles
used for semiquantitative RT-PCR (30, 35, 33, 30, and 22 cycles,
respectively) was chosen on the basis of pilot experiments (data not
shown). Then aliquots of each reaction were run on 4%
acrylamide-bisacrylamide gels. The gels were
dried and exposed to X-OMAT AS films (Eastman Kodak Company).
Autoradiograms were quantified by scanning densitometry
(Molecular Dynamics).
ACE, Angiotensinogen, and AT1 Receptor
Immunohistochemical Studies
All immunohistochemical studies were performed by the
avidin-biotin complex method, as described previously.8 14
Immunolocalization of ACE was performed with a monoclonal mouse
anti-rat ACE antibody (Chemicon; 10 µg/mL),
angiotensinogen with a polyclonal rabbit anti-rat
angiotensinogen antibody (kindly provided by Dr C. Sernia;
500-fold dilution), and AT1 receptor with a
monoclonal mouse anti-rat AT1 receptor (kindly
provided by Dr G.P. Vinson; undiluted). Control slides were treated
with the corresponding nonimmune serum. Biotinylated rabbit anti-mouse
IgG or biotinylated goat anti-rabbit IgG (Dako A/S) was used as a
secondary antibody. The sites of phosphatase activity were visualized
with fast red (for ACE staining; Dako A/S), and the sites of peroxidase
activity were visualized with 3,3'-diaminobenzidine (for
angiotensinogen and AT1 receptor
staining; Sigma). Paraffin-embedded tissue sections were counterstained
with Mayer's hematoxylin (Sigma).
In Situ RT-PCR
The cDNA was generated and then amplified with the use of
the commercial kit Access RT-PCR System (Promega). In situ RT-PCR was
performed essentially as described by Nuovo et al15 with
minor modifications. Briefly, cryostat kidney sections of 5 µm
thickness were air dried, fixed in acetone, and washed in Tris-buffered
saline. Digoxigenin-labeled 11-dUTP (dig-dUTP, Boehringer
Mannheim) was directly incorporated into the PCR products by
addition of 10 µmol/L dig-dUTP to the RT-PCR mixture. The
optimum number of amplification cycles used was chosen on the basis of
pilot experiments that revealed at what time hybridization signal began
to appear within nuclei (data not shown). Colorimetric
detection of PCR products was performed in which the sections were
incubated with an anti-digoxigenin antibody as
described.8
The negative controls included samples pretreated with RNase A (150 µg/mL in 2x SSC) for 20 minutes at 37°C before in situ RT-PCR process or in situ RT-PCR done without primers.
Measurement of ACE Activity
Brush-border membranes were isolated from renal cortex,
and ACE activity was determined in renal brush border and in serum by a
spectrophotometric method (Sigma), as previously
described.5
Statistical Analysis
Results are expressed as mean±SEM. Comparisons between 2
groups were made with the unpaired Student's t test or the
Kruskal-Wallis nonparametric ANOVA test when appropriate.
Differences were considered significant if the P value was
<0.05.
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Results |
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Proteinuria
BSA-overloaded rats developed heavy proteinuria within the first 24 hours (112±37 versus UNX control rats, 2±1 mg/24 h; n=12; P<0.05), peaking on the fourth day (538±89 versus 3±1 mg/24 h; n=12; P<0.05). Proteinuria did not decrease significantly throughout the rest of the study period (at death: 438±49; n=12; P=NS).
Morphological Lesions
At death, BSA-overloaded animals showed dramatic
morphological kidney lesions, with marked interstitial
infiltrate and tubular atrophy and/or vacuolization, and protein casts
within proximal and distal tubules (Figure 1). Only occasional necrotizing
alterations, such as tubular brush-border loss or basement membrane
detachment, were observed, as previously shown.16
BSA-overloaded rats also showed glomerular lesions
consisting of mesangial hypercellularity and matrix
expansion (Figure 1).
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The semiquantification of morphological lesions showed a significant increase in renal injury in BSA-overloaded rats with respect to UNX control animals (UNX control rats, 0.3±0.1; BSA-overloaded rats, 2.3±0.3; n=12; P<0.05).
Expression of RAS Genes in Renal Cortex
As shown in Figure 2 (top panel), a
single band of the corresponding predicted size for each gene was
obtained after RT-PCR on mRNA from renal cortex. Densitometric
analysis of the bands showed an increase in ACE and
angiotensinogen mRNA levels in BSA-overloaded rats compared
with UNX control rats (Figure 2A and B). However, the renin gene
expression was decreased in BSA-overloaded rats compared with UNX
controls (Figure 2C). AT1 receptor mRNA
expression was unchanged in the renal cortex after BSA overload (Figure 2D).
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Renal Distribution of ACE, Angiotensinogen, and
AT1 Receptor Immunoreactivity
In UNX control animals, ACE was mainly localized in proximal
tubules, although it was also detected in glomeruli and in some distal
tubules (Figure 3A and 3C).
BSA-overloaded rats showed a significant increase in the ACE
immunostaining, mainly in the proximal tubular cells
and glomeruli (Figure 3B and 3D). Neither UNX control nor
BSA-overloaded rats showed appreciable immunostaining
of ACE in the renal medulla (data not shown).
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By contrast, angiotensinogen was only localized in the proximal tubules in both UNX control and BSA-overloaded animals. However, the intensity of the staining was much more intense in the latter animals (Figure 4A and 4B).
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In both groups of rats (UNX control and BSA-overloaded), AT1 receptor immunostaining was observed mainly in proximal and distal tubules (Figure 4C and 4D). In addition, cortical and medullary collecting ducts exhibited specific immunoreactivity. Only a weak immunostaining was observed in glomeruli and renal vasculature, probably because of the tissue fixation method.17
Localization of ACE mRNA
Since ACE is the key enzyme in the control of RAS, further studies
were performed to localize its mRNA expression. In situ RT-PCR
demonstrated that the localization of ACE mRNA staining was restricted
to occasional tubular epithelial cells in UNX control rats (Figure 5A and 5C). In BSA-overloaded rats, there
was an increase of the staining signal, especially in the proximal and
distal tubules and in glomerular cells (Figure 5B and 5D). In the majority of the tubular epithelial cells, the
perinuclear distribution of ACE mRNA can be appreciated in both groups
of rats (Figure 5A and 5C). By contrast, no signal was detected
in the inner medulla (not shown). The absence of detectable
hybridization signal in the kidney sections where in situ RT-PCR was
done without primers, as well as the decreased signal in the sections
treated with RNase, confirmed that mRNA had been reverse transcribed
and amplified during the in situ RT-PCR process (not shown).
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ACE Activity in Kidney and Serum
To assess whether the increased ACE gene expression and protein
synthesis corresponded with an increment in the activity of the enzyme,
we determined ACE activity in both cortical brush-border membranes and
serum. ACE activity in renal brush border of protein-overloaded rats
was increased compared with UNX control and normal healthy rats (normal
healthy rats, 2.8±0.7; UNX control rats, 3.1±0.7; BSA-overloaded
rats, 5.5±0.5 U/mg protein x10-4; n=7;
P<0.05). By contrast, serum ACE activity was in the same
range in all groups studied (normal healthy rats, 0.15±0.01; UNX
control rats, 0.14±0.01; BSA-overloaded rats, 0.11±0.01 U/mL; n=7 per
group; P=NS).
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Discussion |
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In the present study we demonstrate that ACE is activated in the kidney of rats with persistent proteinuria. By in situ RT-PCR and immunohistochemistry, increased ACE (both mRNA expression and protein) was mainly localized in proximal and distal tubules of renal cortex and in glomeruli. At the same time, the gene expression of angiotensinogen was increased, that of renin was inhibited, and that of AT1 was unmodified. By immunohistochemistry, angiotensinogen was only located in the proximal tubules, while AT1 was mainly localized in proximal and distal tubules.
Although we have not directly measured the Ang II levels, our data are
not in contrast with an enhanced local Ang II production in the
kidney of BSA-overloaded rats. In fact, in 2-kidney, 1 clip
hypertensive rats and Ang II–infused rats, which show renal renin
depletion, renal Ang II was higher than that found in normal kidneys,
probably because of systemically delivered Ang I, which led to
intrarenally formed Ang II, and because of the existence of
renin-independent mechanisms in the kidney.18 The
angiotensinogen upregulation in the kidney of
BSA-overloaded rats could be due to a direct effect of proteinuria or
to the action of Ang II.18 In cultured renal fibroblasts,
we have reported that angiotensinogen gene expression was
upregulated in response to Ang II.19 A similar phenomenon
has been observed in hepatocytes and cardiac
myocytes.20 21 Unexpectedly, we did not detect alterations
in the AT1 receptor mRNA in the renal cortex
after BSA overload, although it is possible that changes in the Ang II
binding to the AT1 receptor could
occur.22 Furthermore, Ang II downregulates
AT1 receptor in rat vasculature and in cultured
rat mesangial cells, while it upregulates this receptor in
rabbit proximal tubules.23 In addition, we cannot rule out
that cytokines present during renal inflammation may have a
certain role. In fact, interleukin-1
caused an upregulation in
AT1 receptors in rat vascular smooth muscle
cells.24
The incubation of cultured proximal tubular cells with different
proteins, in concentrations found in the urine of patients with
nephrotic syndrome, caused an upregulation in the synthesis of
chemoattractant and vasoactive peptides (MCP-1, RANTES, and
ET-1).1 3 In several experimental models of renal damage,
characterized by heavy and sustained proteinuria, an increase in the
expression of some proinflammatory genes was
demonstrated,2 3 7 suggesting that proteinuria could be
involved in this process. The mechanisms by which proteinuria induces
the expression of a number of genes are unknown. However, the
participation of the nuclear factor-
B (NF-B) has been suggested.
In vitro data show that NF-B could be induced by the stress caused
by protein accumulation in the endoplasmic cell
reticulum.25 In this sense, data from our laboratory have
shown that protein-overloaded rats had an increased NF-B activity in
the renal cortex (R. Largo et al, unpublished data, 1998). In
conjunction with these data, an increased expression of MCP-1 and other
inflammatory genes regulated under the control of NF-B was noted in
the renal cortex of those rats.7 In addition, a role for
NF-B in the gene regulation of angiotensinogen has been
demonstrated.26
The presence of important tubulointerstitial
lesions associated with maintained proteinuria suggests that mediators
generated in proximal tubular cells could be involved in this process.
Locally generated Ang II could be secreted to the
interstitial space, inducing the vasoconstriction of
peritubular vessels with subsequent ischemia. In addition, Ang
II could activate renal interstitial fibroblasts,
inducing several growth-related metabolic events mediated
by the AT1 receptor.19 Moreover, in
vascular smooth muscle cells and mesangial cells, Ang II
caused the activation of NF-B and the production of MCP-1
and other chemokines involved in interstitial mononuclear
cell recruitment.27 28 BSA-overloaded rats have an
accumulation of matrix proteins in the interstitium, as well as
increased synthesis of transforming growth factor-ß (TGF-ß) in the
interstitial and cortical tubular cells.7
Since Ang II may participate in tissue fibrosis through TGF-ß
generation,4 19 29 our data suggest that this vasoactive
peptide could be responsible, at least in part, for the
tubulointerstitial lesions occurring in those
animals. It is also possible that cytokines and growth factors
(TGF-ß, platelet-derived growth factor, ET-1, interleukin-6)
released by Ang II could also have a certain role.29 In
experimental models of renal injury, the treatment with ACE
inhibitors and/or AT1 receptor
antagonist diminished renal TGF-ß, platelet-derived
growth factor, and ET-1 expression, coinciding with an improvement in
renal lesions.4 29 30
In summary, our results show that rats with intense proteinuria have an upregulation of ACE, the key enzyme in the control of the RAS, as well as an upregulation of angiotensinogen. The fact that both proteins were mainly located in the proximal renal tubules suggests that proteinuria may induce the local generation of Ang II and therefore may be responsible for the tubulointerstitial lesions observed in renal diseases associated with persistent proteinuria. On the whole, our data suggest a novel mechanism by which proteinuria may participate in the progression of renal diseases.
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Acknowledgments |
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This work was supported in part by grants from Comunidad Autónoma de Madrid (97/084/0003), Fondo de Investigación Sanitaria (96/2021), Ministerio de Educación y Ciencia (PM 94/211, PM 95/93, PM 97/85, SAF 97/55), EU Concerted Action Grant, BMH4-CT98–3631 (DG 12-SSMI), and Fundación Iñigo Álvarez de Toledo. Drs Largo, Gómez-Garre, and Soto are fellows from Ministerio de Educación y Ciencia, Comunidad Autónoma de Madrid, and Fundación Iñigo Álvarez de Toledo, respectively. Anti-angiotensinogen antibody and anti-AT1 receptor antibody were kindly provided by Drs C. Sernia and G.P. Vinson, respectively.
Received January 8, 1998; first decision February 13, 1998; accepted October 26, 1998.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Remuzzi G, Ruggenenti P, Benigni A. Understanding the nature of renal disease progression. Kidney Int. 1997;51:2–15.[Medline] [Order article via Infotrieve]
2. Burton C, Harris KP. The role of proteinuria in the progression of chronic renal failure. Am J Kidney Dis. 1996;27:765–775.[Medline] [Order article via Infotrieve]
3. Benigni A, Remuzzi G. Glomerular protein trafficking and progression of renal disease to terminal uremia. Semin Nephrol. 1996;16:151–159.[Medline] [Order article via Infotrieve]
4. Egido J. Vasoactive hormones and renal sclerosis: nephrology forum. Kidney Int. 1996;49:578–597.[Medline] [Order article via Infotrieve]
5.
Largo R, Gómez-Garre D, Liu XH, Alonso J, Blanco
J, Plaza JJ, Egido J. Endothelin-1 upregulation in the kidney of
uninephrectomized spontaneously hypertensive rats and its modification
by the angiotensin-converting enzyme inhibitor
quinapril. Hypertension. 1997;29:1178–1185.
6. Harris RC, Cheng HF. The intrarenal renin-angiotensin system: a paracrine system for the local control of renal function separate from the systemic axis. Exp Nephrol. 1996;4:2–7.
7. Eddy AA, Giachelli CM. Renal expression of genes that promote interstitial inflammation and fibrosis in rats with protein-overload proteinuria. Kidney Int. 1995;47:1546–1557.[Medline] [Order article via Infotrieve]
8. Gómez-Garre D, Largo R, Liu XH, Gutiérrez S, López-Armada MJ, Palacios I, Egido J. An orally active ETA/ETB receptor antagonist ameliorates proteinuria and glomerular lesions in rats with proliferative nephritis. Kidney Int. 1996;50:962–972.[Medline] [Order article via Infotrieve]
9. Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987;162:156–159.[Medline] [Order article via Infotrieve]
10.
Ohkubo H, Kageyama R, Ujihara M, Hirose T, Inayama S,
Nakanishi S. Cloning and sequence analysis of cDNA for rat
angiotensinogen. Proc Natl Acad Sci U S A. 1983;80:2196–2200.
11.
Burnham CE, Hawelu-Johnson CL, Frank BM, Lynch KR.
Molecular cloning of rat renin cDNA and its gene. Proc Natl Acad
Sci U S A. 1987;84:5605–5609.
12. Koike G, Krieger JE, Jacob HJ, Mukoyama M, Pratt RE, Dzau VJ. Angiotensin converting enzyme and genetic hypertension: cloning of rat cDNAs and characterization of the enzyme. Biochem Biophys Res Commun. 1994;198:380–386.[Medline] [Order article via Infotrieve]
13. Iwai N, Yamano Y, Chaki S, Konishi F, Bardhan S, Tibbetts C, Sasaki K, Hasegawa M, Matsuda Y, Inagami T. Rat angiotensin II receptor: cDNA sequence and regulation of the gene expression. Biochem Biophys Res Commun. 1991;177:299–304.[Medline] [Order article via Infotrieve]
14. Morrell NW, Atochina EN, Morris KG, Danilov SM, Stenmark KR. Angiotensin converting enzyme expression is increased in small pulmonary arteries of rats with hypoxia-induced pulmonary hypertension. J Clin Invest. 1995;96:1823–1833.
15. Nuovo GJ, Gorgone GA, MacConnell P, Margiotta M, Gorevic PD. In situ localization of PCR-amplified human and viral cDNAs. PCR Methods Appl. 1992;2:117–123.[Medline] [Order article via Infotrieve]
16. Kees-Folts D, Sadow JL, Schreiner GF. Tubular catabolism of albumin is associated with the release of an inflammatory lipid. Kidney Int. 1994;45:1697–1709.[Medline] [Order article via Infotrieve]
17.
Harrison-Bernard LM, Navar LG, Ho MM, Vinson GP,
El-Dahr SS. Immunohistochemical localization of Ang II AT1 receptor in
adult rat kidney using a monoclonal antibody. Am J
Physiol. 1997;273:F170–F177.
18. Navar LG, Imig JD, Zou L, Wang CT. Intrarenal production of angiotensin II. Semin Nephrol. 1997;5:412–422.
19. Ruiz-Ortega M, Egido J. Angiotensin II modulates cell growth-related events and synthesis of matrix proteins in renal interstitial fibroblasts. Kidney Int. 1997;52:1497–1510.[Medline] [Order article via Infotrieve]
20.
Klett C, Nobiling R, Gierschik P, Hackenthal E.
Angiotensin II stimulates the synthesis of
angiotensinogen in hepatocytes by inhibiting
adenylcyclase activity and stabilizing angiotensinogen
mRNA. J Biol Chem. 1993;268:25095–25107.
21.
Sadoshima J, Izumo S. Molecular characterization of
angiotensin II–induced hypertrophy of cardiac
myocytes and hyperplasia of cardiac fibroblasts: critical role of the
AT1 receptor subtype. Circ Res. 1993;73:413–423.
22. Kontogiannis J, Burns KD. Role of AT1 angiotensin II receptors in renal ischemic injury. Am J Physiol. 1998;274:F79–F90.
23. Cheng HF, Becker BN, Burns KD, Harris RC. Angiotensin II upregulates type-1 angiotensin II receptors in renal proximal tubule. J Clin Invest. 1995;95:2012–2019.
24.
Sasamura H, Nakazato Y, Hayashida T, Kitamura Y,
Hayashi M, Saruta T. Regulation of vascular type 1
angiotensin receptors by cytokines.
Hypertension. 1997;30:35–41.
25.
Pahl HL, Baeuerle PA. A novel signal transduction
pathway from the endoplasmic reticulum to the nucleus is mediated by
transcription factor NF-B. EMBO J. 1995;14:2580–2588.[Medline]
[Order article via Infotrieve]
26.
Ron D, Brasier AR, Wright KA, Tate JE, Habener JF. An
inducible 50-kilodalton NF kappa B-like protein and a constitutive
protein both bind the acute-phase response element of the
angiotensinogen gene. Mol Cell Biol. 1990;10:1023–1032.
27.
Hernández-Presa MA, Bustos C, Ortego M,
Tuñón J, Renedo G, Ruiz-Ortega M, Egido J.
Angiotensin-converting enzyme inhibition prevents
arterial nuclear factor-B activation, monocyte
chemoattractant protein-1 expression, and macrophage
infiltration in a rabbit model of early accelerated
atherosclerosis. Circulation. 1997;95:1532–1541.
28.
Ruiz-Ortega M, Bustos C, Hernández-Presa MA,
Lorenzo O, Plaza JJ, Egido J. Angiotensin II participates
in mononuclear cell recruitment in the kidney through nuclear
factor-kappa B activation and monocyte chemoattractant protein-1 gene
expression. J Immunol. 1998;161:430–439.
29. Dubey RK, Jackson EK, Rupprecht HD, Sterzel RB. Factors controlling growth and matrix production in vascular smooth muscle and glomerular mesangial cells. Curr Opin Nephrol Hypertens. 1997;6:88–105.[Medline] [Order article via Infotrieve]
30. Matsusaka T, Hymes J, Ichikawa I. Angiotensin in progressive renal diseases: theory and practice. J Am Soc Nephrol. 1996;7:2025–2043.[Abstract]
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 W. A. Windt, J. Prakash, R. J. Kok, F. Moolenaar, C A. Kluppel, D. de Zeeuw, R. P. van Dokkum, and R. H Henning Renal targeting of captopril using captopril-lysozyme conjugate enhances its antiproteinuric effect in adriamycin-induced nephrosis Journal of Renin-Angiotensin-Aldosterone System, December 1, 2004; 5(4): 197 - 202. [Abstract] [PDF]
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S. Mezzano, C. Aros, A. Droguett, M. E. Burgos, L. Ardiles, C. Flores, H. Schneider, M. Ruiz-Ortega, and J. Egido NF-{kappa}B activation and overexpression of regulated genes in human diabetic nephropathy Nephrol. Dial. Transplant., October 1, 2004; 19(10): 2505 - 2512. [Abstract] [Full Text] [PDF]
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 M. L. Graciano, R. d. C. Cavaglieri, H. Delle, W. V. Dominguez, D. E. Casarini, D. M. A. C. Malheiros, and I. L. Noronha Intrarenal Renin-Angiotensin System Is Upregulated in Experimental Model of Progressive Renal Disease Induced by Chronic Inhibition of Nitric Oxide Synthesis J. Am. Soc. Nephrol., July 1, 2004; 15(7): 1805 - 1815. [Abstract] [Full Text] [PDF]
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 N. Tejera, D. Gomez-Garre, A. Lazaro, J. Gallego-Delgado, C. Alonso, J. Blanco, A. Ortiz, and J. Egido Persistent Proteinuria Up-Regulates Angiotensin II Type 2 Receptor and Induces Apoptosis in Proximal Tubular Cells Am. J. Pathol., May 1, 2004; 164(5): 1817 - 1826. [Abstract] [Full Text] [PDF]
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 H. T. Yu Progression of Chronic Renal Failure Arch Intern Med, June 23, 2003; 163(12): 1417 - 1429. [Abstract] [Full Text] [PDF]
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H. Bos, G. D Laverman, R. H Henning, A. T. Tiebosch, P. E de Jong, D. de Zeeuw, and G. Navis Involvement of renal ACE activity in proteinuria-associated renal damage in untreated and treated adriamycin nephrotic rats Journal of Renin-Angiotensin-Aldosterone System, June 1, 2003; 4(2): 106 - 112. [Abstract] [PDF]
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L. E Deelman, G. Navis, E. de Boer, M. Wietses, D. de Zeeuw, and R. H Henning Role of proteinuria in the regulation of renal renin-angiotensin system components in unilateral proteinuric rats Journal of Renin-Angiotensin-Aldosterone System, March 1, 2003; 4(1): 38 - 42. [Abstract] [PDF]
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 M. Morcos, A. A.R. Sayed, A. Bierhaus, B. Yard, R. Waldherr, W. Merz, I. Kloeting, E. Schleicher, S. Mentz, R. F. Abd el Baki, et al. Activation of Tubular Epithelial Cells in Diabetic Nephropathy Diabetes, December 1, 2002; 51(12): 3532 - 3544. [Abstract] [Full Text] [PDF]
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V. Alvarez, Y. Quiroz, M. Nava, H. Pons, and B. Rodriguez-Iturbe Overload proteinuria is followed by salt-sensitive hypertension caused by renal infiltration of immune cells Am J Physiol Renal Physiol, November 1, 2002; 283(5): F1132 - F1141. [Abstract] [Full Text] [PDF]
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A. Nishiyama, D. M. Seth, and L. G. Navar Renal Interstitial Fluid Angiotensin I and Angiotensin II Concentrations during Local Angiotensin-Converting Enzyme Inhibition J. Am. Soc. Nephrol., September 1, 2002; 13(9): 2207 - 2212. [Abstract] [Full Text] [PDF]
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A. Smit-van Oosten, R. H Henning, and H. van Goor Strain differences in angiotensin-converting enzyme and angiotensin II type I receptor expression. Possible implications for experimental chronic renal transplant failure Journal of Renin-Angiotensin-Aldosterone System, March 1, 2002; 3(1): 46 - 53. [Abstract] [PDF]
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H. Okada, T. Inoue, Y. Kanno, T. Kobayashi, Y. Watanabe, J. B. Kopp, R. M. Carey, and H. Suzuki Interstitial Fibroblast-Like Cells Express Renin-Angiotensin System Components in a Fibrosing Murine Kidney Am. J. Pathol., March 1, 2002; 160(3): 765 - 772. [Abstract] [Full Text] [PDF]
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C. Dechow, C. Morath, J. Peters, I. Lehrke, R. Waldherr, V. Haxsen, E. Ritz, and J. Wagner Effects of all-trans retinoic acid on renin-angiotensin system in rats with experimental nephritis Am J Physiol Renal Physiol, November 1, 2001; 281(5): F909 - F919. [Abstract] [Full Text] [PDF]
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I. LEHRKE, R. WALDHERR, E. RITZ, and J. WAGNER Renal Endothelin-1 and Endothelin Receptor Type B Expression in Glomerular Diseases with Proteinuria J. Am. Soc. Nephrol., November 1, 2001; 12(11): 2321 - 2329. [Abstract] [Full Text] [PDF]
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Y. Suzuki, O. Lopez-Franco, D. Gomez-Garre, N. Tejera, C. Gomez-Guerrero, T. Sugaya, R. Bernal, J. Blanco, L. Ortega, and J. Egido Renal Tubulointerstitial Damage Caused by Persistent Proteinuria Is Attenuated in AT1-Deficient Mice : Role of Endothelin-1 Am. J. Pathol., November 1, 2001; 159(5): 1895 - 1904. [Abstract] [Full Text] [PDF]
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 S. A. Mezzano, M. Ruiz-Ortega, and J. Egido Angiotensin II and Renal Fibrosis Hypertension, September 1, 2001; 38(3): 635 - 638. [Abstract] [Full Text] [PDF]
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A. J. P. Lewington, M. Arici, K. P. G. Harris, N. J. Brunskill, and J. Walls Modulation of the renin-angiotensin system in proteinuric renal disease: are there added benefits? Nephrol. Dial. Transplant., May 1, 2001; 16(5): 885 - 888. [Full Text] [PDF]
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D. Gomez-Garre, R. Largo, N. Tejera, J. Fortes, F. Manzarbeitia, and J. Egido Activation of NF-{{kappa}}B in Tubular Epithelial Cells of Rats With Intense Proteinuria : Role of Angiotensin II and Endothelin-1 Hypertension, April 1, 2001; 37(4): 1171 - 1178. [Abstract] [Full Text] [PDF]
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 H. Zhang, J. Wada, K. Hida, Y. Tsuchiyama, K. Hiragushi, K. Shikata, H. Wang, S. Lin, Y. S. Kanwar, and H. Makino Collectrin, a Collecting Duct-specific Transmembrane Glycoprotein, Is a Novel Homolog of ACE2 and Is Developmentally Regulated in Embryonic Kidneys J. Biol. Chem., May 11, 2001; 276(20): 17132 - 17139. [Abstract] [Full Text] [PDF]
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