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(Hypertension. 1997;29:1178-1185.)
© 1997 American Heart Association, Inc.
Articles |
Endothelin-1 Upregulation in the Kidney of Uninephrectomized Spontaneously Hypertensive Rats and Its Modification by the Angiotensin-Converting Enzyme Inhibitor Quinapril
From the Renal Research Laboratory Fundación Jiménez Díaz, Universidad Autónoma, and the Department of Pathology (J.B.), Hospital Clínico, Universidad Complutense, Madrid, Spain.
Correspondence to Jesús Egido, MD, Servicio Nefrologia, Fundación Jiménez Díaz, Avda Reyes Católicos, 2, 28040 Madrid. E-mail egido{at}alpha2.ft.uam.es
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Abstract |
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Abstract Endothelin (ET-1) is a potent vasoconstrictor that plays an important role in the control of renal circulation and tubular function. The contribution of this peptide to the pathogenesis of systemic hypertension and renal failure remains largely undefined. In spontaneously hypertensive rats (SHR) uninephrectomized at 20 weeks of age (UNX-SHR) and followed until 45 weeks of age, we determined ET-1 gene expression in renal tissue by reverse transcription–polymerase chain reaction and its localization by in situ hybridization in paraffin-embedded kidney sections. Age-matched SHR and normotensive Wistar-Kyoto (WKY) rats were chosen as controls. At the end of the follow-up, UNX-SHR had high systolic blood pressure, intense proteinuria, mesangial expansion, focal and segmental glomerular sclerosis, and tubulointerstitial lesions. In relation to WKY and SHR, UNX-SHR exhibited an increase in ET-1 gene expression in renal cortex and medulla. By in situ hybridization and immunoperoxidase staining, an overexpression of ET-1 gene and protein were seen in mesangial and glomerular epithelial cells and in some proximal tubules and vessels. Angiotensin-converting enzyme (ACE) activity was significantly increased in the renal brush border. Since in mesangial cells, angiotensin II induces ET-1 synthesis, a group of UNX-SHR received the ACE inhibitor quinapril from the time of UNX. These animals had a decrease in blood pressure, proteinuria, and serum and brush border ACE activity and in the expression and synthesis of ET-1 in all renal areas. On the whole, these data show that UNX-SHR have an upregulation of ET-1 gene and protein in several structures of the kidney compared with SHR and WKY rats. Quinapril diminished ACE activity and ET-1 expression and synthesis coincidentally with an improvement in proteinuria and morphological lesions. The beneficial effects of ACE inhibitors may be due to the diminution of both angiotensin II and ET-1 generation.
Key Words: kidney • rats, inbred SHR • endothelin-1 • ACE inhibition
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Introduction |
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Endothelin 1 is a potent vasoconstrictor peptide1 that can be synthesized by numerous cells, including renal glomerular mesangial and epithelial cells and tubular epithelial cells. ET-1 modulates blood pressure and extracellular volume by exerting a broad range of actions on multiple tissues, including the kidney.2 3 4 However, the role of ET-1 in hypertension remains unclear. Although intravenous ET-1 administration causes a reversible and salt-dependent hypertension in rats,5 6 both patients with essential hypertension and SHR have ET-1 serum levels in the normal range in most of the studies (reviewed in Reference 77 ). Hughes et al8 found that SHR and age-matched WKY had no difference in renal ET-1 levels until hypertension appeared. In this time, SHR had significantly reduced ET-1 in the urine and in the outer and inner medulla. Furthermore, an increased renal vasoconstriction in response to exogenous ET-1 was found in SHR compared with normotensive WKY.9 10
The renin-angiotensin system has been implicated in the pathogenesis of hypertension and renal damage progression in SHR.11 The relationship between Ang II and ET-1 has been clearly established.12 4 Ang II induces ET-1 gene expression and the release of the corresponding peptide in cultured heart endothelial cells13 and in mesangial cells.14 ET-1 also increments ACE activity in cultured endothelial cells.15
The SHR is considered an appropriate animal model to study the effect of prolonged hypertension in renal disease. Although renal injury is not evident early,16 SHR develop severe systemic hypertension and progressive glomerulosclerosis over the years. After UNX, this process is accelerated, and the animals develop glomerular capillary hypertension, proteinuria, glomerulosclerosis, and progressive renal injury.17 18
Therefore, the aims of this work were twofold: first, to study the expression of ET-1 gene and its corresponding protein in the kidney of SHR and UNX-SHR; and second, to examine whether the administration of quinapril, an ACE inhibitor with high tissue binding, might modify the glomerular, vascular, and tubulointerstitial lesions and the ET-1 expression and synthesis in the kidney of UNX-SHR.
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Methods |
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Rats
Male SHR (Iffa Credo) were uninephrectomized at 20 weeks of age. Then they were randomly distributed into two groups: group 1, no therapy; and group 2, 200 mg/L quinapril (a gift from Parke Davis as powdered hydrochloride salt) added to the drinking water and replaced each 48 hours. Age-matched SHR and WKY rats were used as controls. Rats were allowed free access to water and standard rat chow. Every other week, animals were placed in metabolic cages, and 24-hour urine samples were collected for measurement of protein concentration by the sulfosalicylic acid method. At the same intervals, SBP was measured by tail-cuff sphygmomanometer (NARCO Biosystems). The blood pressure value for each rat was calculated as the average of three separate measurements at each session.
At 45 weeks of age, all rats, n=4 per group, were anesthetized with pentobarbital sodium (5 mg/100 g body wt) and killed. Blood was collected for ACE activity measurement and, after perfusion with cold sodium saline, kidneys were removed and processed for various studies.
Morphological Studies
Renal cortex and medulla were rapidly separated by fine
dissection, fixed in buffered formalin, and embedded in paraffin.
Sections were prepared and stained with hematoxylin-eosin and Masson's
trichrome. Semiquantitative evaluation of histological
damage was performed by two observers in a blinded fashion.
Glomerular damage, tubular changes,
interstitial fibrosis, and inflammation were graded
from - to 4+ (-, no changes; 1+, changes affecting <25% of
sample; 2+, changes affecting 25% to 50% of sample; 3+, changes
affecting 51% to 75% of sample; and 4+, changes affecting >75% of
sample).
Measurement of ACE Activity
Brush-border membranes were isolated from renal cortex by the
method of Malathi et al.19 The final pellet containing the
brush borders was resuspended and diluted in 0.3% Triton X-100 and
then stored at -80°C until used for enzyme activity measurement. The
brush-border preparation was characterized by dosage-specific enzyme
markers.19
ACE activity was determined in renal brush border and in serum samples by a spectrophotometric method (Sigma Chemical Co) as previously described.20 In brush-border membranes, ACE activity is expressed as relative units per milligram of protein, determined by the Lowry method,21 and in serum as units per milliliter.
RNA Extraction, RT, and PCR
Pieces of renal cortex and medulla were snap-frozen in liquid
nitrogen and stored at -80°C until study. Then tissue was
homogenized, and total RNA was obtained by the acid
guanidinium-phenol-chloroform method.22 RT was performed
with a cDNA synthesis kit (Promega). PCR was carried out with rat
preproET-1– and GAPDH-specific primers (Ramón Cornet) as
described.23 Then PCR-amplified products were
electrophoresed and transferred onto nylon membranes (Genescreen,
DuPont). Autoradiograms were scanned with the Image
Quant densitometer (Molecular Dynamics). Results were expressed as
arbitrary densitometric units.
In Situ Hybridization
Digoxigenin-labeled single-strand RNA probes of preproET-1 were
prepared with a nonradioactive RNA labeling kit (Boehringer
Mannheim). Sense and antisense preproET-1 riboprobes were synthesized
from the linearized plasmid vector PMAM neoblue containing a 180-bp
fragment of the rat preproET-1 (a gift from Dr Derek Nuñez,
Cambridge, UK).
Tissue sections were deparaffinized, rehydrated, and fixed with paraformaldehyde-glutaraldehyde. Then tissue was pretreated,23 and hybridization was carried out at 42°C overnight. Tissues were washed in high-stringency conditions. Hybridization was then revealed and, after washing, coverslips were applied before microscopic examination.
Tissue Localization of Endothelin-Like Immunoreactivity
For the immunohistochemical analysis, paraffin-embedded
kidney sections were mounted on polylysine-treated slides.
Immunoperoxidase staining was performed with a rabbit polyclonal ET-1
antiserum (Peninsula Laboratories) by the avidin-biotin complex method
as we described previously.23 After peroxidase activity
visualization, sections were contrasted with Mayer's hematoxylin
(Sigma) and analyzed. Immunostaining was graded
as -, no staining; 1+, mild staining; 2+, moderate staining; and 3+,
intense staining. The localization of the reaction was referred to as
glomerular tuft, Bowman's capsule, and peritubular and
perivascular capillaries. All these studies were performed without the
observer knowing to which group the animals belonged (blind study).
Statistical Analysis
Results are expressed as mean±SEM. Comparisons between two
groups were made by the unpaired t test when appropriate.
Data from multiple groups were compared by the Kruskal-Wallis
nonparametric ANOVA test and the Tukey-Kramer test for
multiple comparisons. Differences were taken as significant at a value
of P<.05.
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Results |
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SBP and Proteinuria
Fig 1
summarizes mean±SEM values for SBP and
proteinuria measured every other week until the animals were killed. No
appreciable changes existed in the SBP levels of WKY rats, which were
in the normal range during the whole period of study (not shown).
Severe hypertension was already present in SHR by the time of the
initial SBP determination at 21 weeks (Fig 1A). SBP did not change
significantly after UNX. Proteinuria increased significantly in the
UNX-SHR group (UNX-SHR, 80±5 versus SHR, 24±7 and WKY, 8±2 mg/24 h
at the end of the study; P<.05, n=4) (Fig 1B). The
administration of quinapril was associated with a reduction in SBP
(treated UNX-SHR, 158±3 versus untreated UNX-SHR, 239±4 mm Hg
at the end of the study; P<.05, n=4) and in proteinuria
(treated UNX-SHR, 25±2 versus untreated, 80±5 mg/24 h at the end of
the study; P<.05, n=4).
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), UNX-SHR (
), and treated
UNX-SHR (
). Quinapril treatment diminished SBP since first week
of administration. B, Urinary protein excretion rate during period of
observation. Proteinuria in SHR, UNX-SHR, and treated UNX-SHR. UNX-SHR
developed intense proteinuria, reaching a value of 80±6.7 mg/d.
Quinapril treatment prevented development of proteinuria (25±2 mg/d at
end of study). P<.05 vs untreated animals. Data are shown
as mean of each group±SEM. n=4 animals per group.
Pathological Findings
Previous works have described in detail the renal morphological
changes occurring in SHR.18 24 25 At the end of our study,
the UNX-SHR presented segmental and global
glomerular sclerosis and arterioarteriolar sclerosis
associated with interstitial cell infiltration and
fibrosis, tubular atrophy, and dilatation with occasional intratubular
casts. In addition, these animals demonstrated marked medial and
intimal thickening with hyalinosis (Table 1 and Fig 2). Quinapril-treated UNX-SHR presented a
dramatic decrease in renal damage. Glomerular sclerosis or
hyalinization was undetectable, and tubular and
interstitial damage was completely prevented (Table 1 and
Fig 2). Interestingly, in some of these animals there was no evidence
of vascular alterations, whereas in others there was a discrete
increase in media and intima thickness (not shown).
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ACE Activity in Serum and Kidney Cortex
To verify whether animals had drunk quinapril, we measured ACE
activity in serum and kidney brush-border membranes. As previously
pointed out,20 kidney ACE activity is localized primarily
in this region. Compared with SHR, UNX-SHR showed a slight decrease in
serum ACE activity (Fig 3, left). Brush-border ACE
activity was greater in UNX-SHR than in SHR (Fig 3, right). In rats
receiving quinapril, ACE activity was almost completely inhibited in
serum (84%), whereas it was decreased by 
53% in the brush border
(P<.05 in both cases compared with untreated UNX-SHR).
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ET-1 mRNA Expression in the Kidney
Fig 4 (top) shows a PCR analysis of the
ET-1 gene expression in the kidney from a
representative rat of each group. The expression of the
ET-1 gene in cortex was similar in SHR and WKY, but in agreement with
previous results,26 it was significantly lower in the
renal medulla of SHR (Fig 4, bottom). However, in UNX-SHR, ET-1 gene
expression was increased both in cortex (2.5-fold) and in medulla
(2.7-fold) compared with SHR (Fig 4). The administration of quinapril
to UNX-SHR decreased ET-1 mRNA expression in both areas (Fig 4). In
addition, in a parallel study, the administration of quinapril to
UNX-SHR at a dose of 100 mg/L (n=4) induced only a partial diminution
in SBP (180±3 versus 239±4 mm Hg in untreated UNX-SHR), whereas
proteinuria and ET-1 mRNA expression in renal cortex were similar to
those obtained with the higher dose of the ACE inhibitor
(26±3 mg/d and 0.96±0.2 AU, respectively).
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In Situ Hybridization
The cellular distribution of the ET-1 mRNA in the kidneys of
animals from different groups was investigated by in situ hybridization
with a digoxigenin-labeled riboprobe. In SHR kidneys, labeling was
detected in glomerular cells (mesangial,
endothelial, parietal, and visceral epithelial cells)
and in the luminal pole of some proximal tubular cells (Fig 5A). The endothelium of some peritubular
capillaries and arteries and the adventitia were intensely stained (not
shown). In the UNX-SHR, the renal distribution of labeling was nearly
identical to that of SHR but much more intense (Fig 5B). A marked
diminution of ET-1 mRNA expression in all renal areas was observed in
quinapril-treated UNX-SHR compared with untreated UNX-SHR (Fig 5C).
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Nonspecific hybridization signal was assessed by the following negative controls: sections treated with RNase before hybridization with the ET-1 mRNA probe, sections hybridized with the sense probe, and sections hybridized in the absence of antisense probe or anti-digoxigenin antibody (not shown).
ET-1 Immunostaining
ET-1 immunoreactivity was identified in renal cortex and medulla.
In WKY, the staining was localized in different renal areas (Fig 6A and 6B), especially in the medulla, where it was even higher
than that seen in SHR (Fig 6C and 6D). In the glomeruli of UNX-SHR, a
fine granular immunostaining was localized in a patchy
distribution in glomerular capillary walls,
mesangial regions, and glomerular epithelial
cells (Fig 6E and 6F). Prominent immunostaining was
also detected in the endothelium of some peritubular
capillaries and small to medium-size arteries. Occasionally, an intense
cell infiltration was localized around the medium-size renal arteries
of UNX-SHR.
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The administration of quinapril to UNX-SHR diminished ET-1 protein in
the different structures of the kidney (Fig 6G
and 6H). A
semiquantitative evaluation of ET-1 immunostaining is
shown in Table 2.
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Discussion |
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The results of the present study demonstrate three major points: (1) By 45 weeks of age, the SHR uninephrectomized at 20 weeks presented renal changes associated with markedly elevated proteinuria and morphological evidence of severe hypertensive nephrosclerosis; (2) at the time they were killed, the kidney from 45-week-old UNX-SHR showed increased expression of the ET-1 gene and the corresponding protein; and (3) ACE inhibition prevented the development of proteinuria and morphological changes, coinciding with a marked decrease in renal ET-1 gene expression and ET-1 synthesis.
Besides the vasoactive properties of ET-1, this hormone induces mesangial cell proliferation and synthesis of matrix proteins.27 Therefore, it has been suspected that during renal injury, the augmentation of ET-1 synthesis could potentially contribute to glomerular ischemia, mesangial cell proliferation, and accumulation of matrix proteins. The issue of whether increased ET-1 synthesis occurs in vivo has been investigated in a wide range of experimental glomerular diseases. Increases in urinary ET-1 excretion and glomerular ET-1 expression and/or production paralleled the degree of glomerular injury.28 29 30 31 However, the specific cells implicated in the elevated synthesis of ET-1 were not identified in these studies.
Our results unequivocally demonstrate that, in SHR and UNX-SHR, ET-1 mRNA was expressed not only in the brush border of tubular epithelial cells and in the endothelium but also in the glomeruli, probably by endothelial, mesangial, and epithelial cells. These data agree with in vitro studies demonstrating that under appropriate stimuli, these cells can express the ET-1 gene.13 14 32 However, a diminution in ET-1 gene expression was observed in the medulla of SHR compared with WKY, in accordance with the decreased staining for ET-1 in this area described in previous studies.33 Recently, low levels of ET-1 mRNA, assessed by PCR, in the inner medulla were found only after the appearance of hypertension.8 Although the pathophysiological significance of these findings remains unclear, the results suggest that, by 45 weeks of age, ET-1 does not seem to play an important role in the renal damage of the SHR. In this regard, the administration of bosentan, a dual ETA/ETB receptor antagonist, to young SHR (4 weeks old) for 10 weeks did not prevent the development of hypertension or vascular hypertrophy and remodeling.34 In contrast, UNX-SHR, compared with SHR and WKY, showed an important increase in ET-1 gene and protein expression in all renal structures, coinciding with the maximal proteinuria and morphological lesions.
The factors contributing to the increased ET-1 expression in the kidney of UNX-SHR are not clear. Although in cultured endothelial cells, shear stress and pressure enhanced ET-1 production,35 36 the effect of adaptive changes in the glomerular hemodynamics occurring after renal mass ablation remains to be established. In parallel studies, however, we found that in UNX-WKY animals, ET-1 gene expression did not increase after 2 months of renal ablation, a period during which rats were normotensive and had no proteinuria (not shown). Thus, it seems that UNX per se is not the primary cause of the increased renal ET-1 gene expression detected in the UNX-SHR. In vitro, recent data have also shown that TGF-ß and PDGF stimulate ET-1 gene expression.37 38 Since an upregulation of TGF-ß and PDGF was observed in UNX-SHR,39 one could speculate that these growth factors could contribute to the increased ET-1 expression observed in our study. In agreement with this hypothesis, Mackay et al40 observed in WKY rats a decline in TGF-ß mRNA levels 2 weeks after nephrectomy.
There is a clear relationship between Ang II and ET-1. In cultured endothelial and mesangial cells, Ang II stimulates ET-1 mRNA expression and protein production in a dose- and time-dependent manner.13 14 To further define the implication of locally generated Ang II in the upregulation of ET-1 gene expression, a group of UNX-SHR were treated with quinapril, an ACE inhibitor with high tissue-binding affinity, from the moment of UNX until the time they were killed. The administration of quinapril reduced urinary protein excretion and the semiquantitative score of renal damage, in agreement with previous studies in aged SHR.24 25 Simultaneously, a downregulation in the renal ET-1 gene and protein expression was found, as well as a diminution in brush-border ACE activity with respect to UNX-SHR.
The mechanism of the diminution in the ET-1 gene expression by the ACE inhibitor quinapril is not known. This effect seems to be relatively independent of blood pressure, since the administration of a lower dose of quinapril resulted in a similar downregulation of ET-1 gene expression. We observed the same phenomenon in a normotensive rat model of renal injury receiving quinapril (unpublished data, 1996). Therefore, it is plausible that the diminution in the ET-1 expression could be due to the local inhibition of Ang II generation. In this sense, both the Ang II receptor antagonist losartan and ACE inhibitors reduced proteinuria to a similar extent in the 5/6 renal ablation model.41 42 However, other authors have suggested that the reduction in ET-1 production by endothelial cells may be mediated by bradykinin rather than by Ang II inhibition.43 Finally, the decrease in renal ET-1 expression could be a mere reflection of a lesser kidney damage observed in the treated animals. Further experiments using an Ang II or ET-1 receptor antagonist could help to unravel this issue.
On the whole, these data show that UNX-SHR have overexpression of the ET-1 gene and protein in several structures of the kidney. Quinapril diminishes ACE activity and ET-1 mRNA expression in the kidney coincidentally with an improvement in clinical and morphological lesions. ACE inhibitors may be effective in this and other clinical conditions by modifying Ang II and ET-1 generation.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by grants from Fondo de Investigaciones Sanitarias de la Seguridad Social (FIS) (92/592, 93/834, 94/370, and 96/2021), Ministerio de Educación y Ciencia (PM 92/42, PM 94/211, and PM 95/93), and Fundación Iñigo Álvarez de Toledo. Drs Largo and Alonso are fellows of FIS; Dr Gómez-Garre is a fellow of Fundación Iñigo Álvarez de Toledo; and Dr Liu is a visiting fellow from the University of Beijing, PRC. The color reproductions were kindly funded by Parke Davis, SL, Spain. We thank Dr Gloria Pérez-Tejerizo for her technical assistance and Dr Carlos Guijarro for reading the manuscript.
Received April 11, 1996; first decision May 13, 1996; accepted October 29, 1996.
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