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1 Research Group for Paediatrics and Nephrology, Hungarian Academy of Sciences, Budapest, Bókay u 53, Hungary, H-10832 1st Department of Paediatrics, Semmelweis University, Budapest, Bókay u 53, Hungary, H-10833 Department of General Zoology, Eötvös University of Sciences, Budapest, Pázmány Péter sétány 12, Hungary, H-11174 2nd Department of Pathology, Semmelweis University, Budapest, Üllöi u 93, Hungary, H-1095 Department of Pulmonology, Semmelweis University, Budapest, Diósárok u 1/C, Hungary, H-1125
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Abstract |
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(Received 26 February 2004;
accepted after revision 26 April 2004; first published online 6 May 2004)
Corresponding author A. Vannay: 1st Department of Paediatrics, Semmelweis University, 1083 Budapest, Bókay J. u. 53-54, Hungary. Email: vannay{at}gyer1.sote.hu
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Introduction |
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Recent findings indicate that VEGF is not only a potent vascular permeability and angiogenic regulator but also regulates many endothelial cell functions. VEGF inhibits vascular smooth muscle cell proliferation (Laitinen et al. 1997), enhances endothelial cell survival (Gerber et al. 1998), suppresses thrombosis (Waltham et al. 2003) and exerts anti-inflammatory effects (Scalia et al. 1999). Moreover, VEGF induces the synthesis of vasodilating agents such as nitric oxide and prostacyclin (Murohara et al. 1998; He et al. 1999) in endothelial cells. These effects are likely to be involved in VEGF-associated vascular protection.
Previous studies performed on a variety of cultured cells demonstrated that VEGF mRNA and protein expression are markedly increased by hypoxia (Shweiki et al. 1992; Ladoux & Frelin, 1993) and different cytokines (Gloddek et al. 1999; Finkenzeller et al. 1992; Stavri et al. 1995; Dankbar et al. 2000; Levitas et al. 2000). In vivo studies have also shown that VEGF mRNA and protein expression are increased in response to ischaemic injury of different organs (Banai et al. 1994; Bernaudin et al. 2002). However, data about ischaemia-induced renal VEGF synthesis are contradictory. While Kanellis and colleagues found no alteration, we have previously observed increased VEGF protein levels (Kanellis et al. 2000, 2002; Vannay et al. 2004).
As VEGF may support post-ischaemic recovery of the kidney, the aim of the present study was to analyse the renal synthesis and immunohistochemical localization of VEGF in a rat model of I/R-induced ARF. We also investigated the renal mRNA expression of IL-6 and IL-1ß, which are implicated in the regulation of VEGF synthesis (Glodddek et al. 1999; Dankbar, 2000; Levitas, 2000).
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Methods |
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The Institutional Committee on Animal Welfare approved all experiments. The experiments were performed on sexually mature, male Wistar rats (body weight, 200–250 g). Animals were housed in a temperature-controlled (22 ± 1 °C) room with 12 h alternating light and dark cycles. Animals had free access to standard rat chow and water.
Surgical procedure was performed as previously described (Muller et al. 2002). Briefly, animals were anaesthetized by intraperitoneal injection of pentobarbital sodium (50 mg (kg body weight)–1; Nembutal, Abbott Laboratories, Abbott Park, IL, USA) and were placed on a thermocontrolled table to maintain rectal temperature at 37 ± 1 °C. After performing a midline abdominal incision, the left renal pedicle was isolated and occluded with an atraumatic microvascular clamp for 55 min. During ischaemia the abdomen was temporarily closed. Before the end of the ischaemic period the right kidneys were removed. After removing the microvascular clamp the abdomen was closed, and the animals remained on thermocontrolled tables until complete recovery from anaesthesia. Control animals underwent identical surgical procedure without occlusion of the left renal pedicle.
Groups of animals were killed by bleeding from the abdominal aorta after isolation, but before clamping of the left renal pedicle (n= 6) and at 2 h (n= 6) and 24 h (n= 6) after reperfusion. Blood was collected for separation of serum and the left kidneys were removed. Kidney segments were immediately frozen in liquid nitrogen or fixed in formalin (4%, pH 7.4).
Renal function
Serum creatinine and blood urea nitrogen concentrations were determined photometrically using a commercially available test (F. Hoffmann-la Roche Ltd, Basel, Switzerland) on a Hitachi 717 automated spectrophotometer.
RNA isolation and RT-PCR
RNA isolation and RT-PCRs were performed as previously described (Losonczy et al. 2000). Briefly, total RNA was isolated from kidney samples by RNeasy Total RNA Isolations Kit (Qiagen GmbH, Hilden Germany), according to the manufacturer's instructions. Quality and quantity of the RNA were photometrically confirmed. One microgram of total RNA was reverse-transcripted using SuperScript II RNase H– (Gibco/BRL, Eggenstein, Germany) to generate first-strand cDNA.
The PCRs were performed in a final volume of 50 µl containing 10% 10x PCR buffer, 2 mM MgCl2, 0.2 mM dNTP mixture, 1.5 U Ampli Taq DNA polymerase (Gibco/BRL) and sense and antisense primers (0.5 µM of each). Specific primer pairs for rat VEGF and IL-1ß were selected by using DNAstar (gene bank accession numbers: AF215725 [GenBank] for VEGF and E01884 [GenBank] for IL-1ß). The primer pairs for VEGF fit to the common region of the different VEGF isoforms and results in one band during amplification. The sequences of the specific primer pairs for VEGF, IL-6 (Siegling et al. 1994), IL-1ß and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (Strehlau et al. 1997) are presented in Table 1.
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Protein isolation and Western blotting
Kidney samples (100 mg) were solubilized in a sample buffer containing (mM): Tris-HCl 100 (pH 8.0), EGTA 1, NaF 5, phenylmethylsulfonyl fluoride (PMSF) 1 and sodium orthovanadate (Na3VO4) 10; with 10 µg ml–1 leupeptin, 10 µg ml–1 aprotinin and 1% Triton X-100 (all chemicals were purchased from Sigma Chemical Co, MO, USA). The lysed samples were centrifuged (10 000 g, 5 min, 4 °C) to pellet nuclei and large cellular fragments. Protein concentration of the supernatants was determined by Bradford assay (Bio-Rad Laboratories, Hercules, CA, USA).
Fifteen micrograms of protein samples were separated by 12% SDS-polyacrylamide gel electrophoresis at 120 V and 40 mA for 90 min (Penguin Dual-Gel Water Cooled Systems, Owl, NH, USA). Pre-stained protein mixture (BenchMark, Gibco/BRL) was used as a marker of molecular mass. Then the separated proteins were transferred to nitrocellulose membrane (Hybond ECL, AP Biotech, UK) in transfer buffer containing (mM): Tris (25), glycine (170) and 20% methanol at 70 V, 220 mA for 80 min (MiniTank electroblotter, Owl).
Non-specific binding sites were blocked for 1 h (23 °C) in a blot solution containing 5% non-fat dry milk and PBS. Then blots were incubated for 60 min (23 °C) with mouse monoclonal antibody raised against 1–140 amino acids of the human VEGF (VEGF(C-1), mouse monoclonal IgG2a, Santa Cruz Biothechnology Inc., CA, USA) diluted to 1:500. Blots were then washed and incubated with peroxidase-conjugated secondary antimouse IgG antibody diluted to 1:1000 for 30 min (23 °C) (Sigma Chemical Co). Immunoreactive bands were visualized using the enhanced chemiluminescence (ECL) Western blotting detection protocol (AP Biotech, Buckinghamshire, UK). The negatives were analysed by computerized densitometry.
Immunohistochemical analysis
Immunohistochemistry was performed on paraffin-embedded 5 µm thick tissue sections fixed in formalin (4%, pH 7.4). To demonstrate VEGF immunoreactivity, we used the same mouse monoclonal antibody as for Western blot analysis. After deparaffinating, sections were microwaved for 7 min at 600 W in Tris-buffered saline (pH 8.0). Endogenous peroxidase activity was quenched with 0.03% hydrogen peroxide solution. After washing in PBS the sections were incubated with primary antibody diluted to 1:40 for 1 h at room temperature. For evaluating staining, a peroxidase kit (DAKO, CA, USA) was used. No first antibody control was carried out with the omission of primary antibody. Sections were counter-stained with haematoxylin (Mayers's Lillie's Modification, DAKO, CA, USA) and covered with Vecta Mount mounting medium (Vector Laboratories Inc., CA, USA). Samples were coded and examined by two independent investigators in a blinded fashion.
Histological analysis
Paraffin sections of kidneys fixed in formalin (4%, pH 7.4) were stained with haematoxylin and eosin. Samples were coded and tubular, glomerular and interstitial lesions were scored from 0 to 3 (0, none; 1, mild grade; 2, moderate grade; 3, severe grade).
Statistics
Data are expressed as mean and standard deviation (mean ±S.D.). Statistical analysis was performed by one-way analysis of variance followed by multiple pair-wise comparisons according to the Newman–Keuls test. Histological scores are expressed as median and range. Histological changes were analysed using Kruskal–Wallis test followed by multiple pair-wise comparisons according to Mann–Whitney U test. Data were considered to be significantly different if P was less than 0.05.
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Results |
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Warm ischaemia for 55 min induced acute renal insufficiency as reflected by increased serum creatinine and blood urea nitrogen concentrations. Serum creatinine concentrations were 96 ± 7 and 368 ± 16 µmol l–1 at 2 and 24 h of reperfusion, respectively, as compared to 48 ± 3 µmol l–1 in controls (both T2 and T24P < 0.01 versus control). Blood urea nitrogen concentrations were 7.8 ± 0.8 and 44.8 ± 4.3 mmol l–1 at 2 and 24 h of reperfusion, respectively, versus 4.8 ± 1.2 mmol l–1 in controls (both T2 and T24P < 0.01 versus control).
VEGF, IL-6 and IL-1ß mRNA expression
Figure 1 shows the mRNA expression of VEGF, IL-6 and IL-1ß using RT-PCR as detected in control, T2 and T24 kidneys. VEGF and IL-1ß mRNA expression did not differ in T2 and T24 and control kidneys. IL-6 mRNA expression significantly increased at 2 h of reperfusion (P < 0.01 versus control) and returned to the control value in T24 kidneys.
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Western blot analysis of control and post-ischaemic kidneys with anti-VEGF mouse monoclonal antibody revealed one distinct band at 23 kDa, which may correspond to the VEGF165 monomer (Fig. 2). We found significantly increased VEGF protein levels at 2 h of reperfusion, which remained elevated in T24 kidneys (both P < 0.01 versus control).
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VEGF immunoreactivity was most prominent in the outer medulla of both control and post-ischaemic kidneys. Immunoreactivity was evident in tubular epithelial cells, parietal layer of Bowman's capsule, glomerular capillary tuft, macula densa, transitional epithelium and in the vascular smooth muscle cells. Granular immunoreactivity was detected in the perinuclear region of tubular epithelial cells at each investigated time point.
In control kidneys, VEGF was diffusely present in the cytoplasm of tubular epithelial cells. In T2 kidneys prominent, basolateral localization of VEGF immunoreactivity was observed in the tubular epithelial cells. All tubular segments were involved in the intraepithelial distribution of VEGF. VEGF distribution in the surviving tubular epithelial cells of T24 kidneys was similar to controls, although in a few tubules the basolateral accumulation of VEGF immunoreactiviy was still evident (Fig. 3). Apart from tubular epithelial cells, there was no change in the intracellular distribution of VEGF.
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Histological analysis of control kidneys revealed normal kidney structure, without glomerular, tubular or interstitial lesions. In T2 kidneys, prominent basolateral eosin staining and mild–moderate tubular necrosis of grade 1.5 (1–2) were observed (P < 0.05 versus control and T24 kidney). In T24 kidneys, severe tubular necrosis of grade 3.0 (2–3) was present (P < 0.05 versus control and T2 kidney). Flattening of the tubular epithelial cells was characteristic in both T2 and T24 kidneys. Glomerular and interstitial changes were not present in any of the groups (Fig. 4).
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Discussion |
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protein levels in the post-ischaemic kidney of histamine-pretreated animals (Vannay et al. 2004).
In the present study we characterized the renal synthesis and localization of VEGF in a rat model of I/R-induced ARF. To achieve more pronounced effects we modified our previous experimental model; we applied longer ischaemic time (55 versus 50 min in our previous study or 40 min in the study of Kanellis et al. 2000) and investigated a longer post-ischaemic period (24 h versus 16 or 1.3 h, respectively).
In accordance with previous observations (Kanellis et al., 2000, 2002; Vannay et al. 2004) we did not find increased VEGF mRNA expression after either 2 or 24 h of reperfusion. However, in line with our previous results, we demonstrated increased VEGF protein levels in the post-ischaemic kidneys. This finding does not support that of Kanellis et al. (2000, 2002). The observed discrepancy may be due to different ischaemic and reperfusion periods, and possibly the different rat strains used (Wistar rats versus Sprague-Dawley rats).
Elevation of VEGF protein level in the presence of unchanged mRNA expression suggests that VEGF synthesis is regulated at a post-transcriptional, rather than at transcriptional level in the post-ischaemic rat kidney. In vitro, different mechanisms have been suggested to participate in the post-transcriptional regulation of VEGF synthesis. It has been shown that hypoxia leads to the stabilization of VEGF mRNA, at least in part, by binding to RNA-binding protein HuR (Levy et al. 1998). Moreover, an internal ribosomal entry site (IRES) of the 5' untranslated region of VEGF ensures the translation of VEGF mRNA and increases the efficiency of translation (Stein et al. 1998) even under hypoxic conditions. These mechanisms may underly increased VEGF protein synthesis in the post-ischaemic kidneys without increased VEGF mRNA expression. Therefore, we hypothesize that kidney, similar to other organs (Banai et al. 1994; Bernaudin et al. 2002), responds to I/R injury with increased synthesis of VEGF. However, the dominance of post-transcriptional regulation of VEGF synthesis after hypoxia seems to be uniquely characteristic for the kidney.
Oxygen deficiency is a strong stimulus, but not the only stimulus for enhanced VEGF synthesis. It has been suggested that IL-6 (Takada et al. 1997) and IL-1ß (Haq et al. 1998) are involved in post-ischaemic renal failure and it has also been shown that they increase VEGF synthesis in vitro (Gloddek et al. 1999; Dankbar et al. 2000; Levitas et al. 2000).
In the present study the IL-6 mRNA expression increased simultaneously with VEGF protein level. While the mechanism of hypoxia-induced renal IL-6 expression is still unclear, a possible mechanism may be via transcriptional activation by the nuclear factor-IL-6 motif in the promoter region, as suggested in vitro (Matsui et al. 1999; Yan et al. 1995).
This finding raises the possibility that the synthesis of IL-6 and VEGF might also be inter-related in the post-ischaemic kidney. This hypothesis is supported by recent findings. IL-6 rapidly phosphorylates a translation initiation factor called eukaryotic initiation factor-4E (Yamigiwa et al. 2004), which reportedly increases the translation of VEGF (Crew et al. 2000). Moreover, IL-6 affects the IRES-dependent translation (Yamigiwa et al. 2004), which may be a key element of the VEGF translation under hypoxic conditions (Stein et al. 1998).
Immunohistochemistry revealed the most prominent VEGF immunoreactivity in the outer medulla in both control and post-ischaemic kidneys. The significance of the relative abundance of VEGF in this region is still unclear. However, in terms of oxygen supply the outer medulla is a special region of the kidney (Brezis & Epstein, 1993; Brezis & Rosen, 1995). The partial oxygen pressure is relatively low in this region, even under non-ischaemic conditions, which may induce VEGF synthesis.
Previously, in the post-ischaemic kidney the secretion of VEGF by tubular epithelial cells has been suggested (Kanellis et al. 2000). In our study, similar to previous findings, VEGF immunoreactivity was transiently accumulated after 2 h of reperfusion in the basolateral area of tubular epithelial cells. Ischaemic injury dramatically alters the structure of renal tubular epithelial cells (Abbate et al. 1994; Ashworth & Molitoris, 1999). Previously, similar intracellular distribution of cytoskeletal (Brown et al. 1997) and non-cytoskeletal (Aufricht et al. 1998) proteins were observed in renal tubular epithelial cells after ischaemic damage. Moreover, in our study, eosin staining was also pronounced within the basolateral area of tubular epithelial cells of T2 kidneys. Therefore, it is more likely that the basolateral accumulation of VEGF in the renal tubular epithelial cells may be a consequence of the post-ischaemic cell damage, rather than a sign of VEGF-specific secretion.
In summary, increased VEGF protein levels and unaltered mRNA expression were demonstrated in post-ischaemic kidneys. These data suggest that, unlike in other organs, during renal I/R injury VEGF synthesis in kidneys is primarily regulated post-transcriptionally. As IL-6 mRNA expression increased simultaneously with VEGF protein levels, the post-ischaemic regulation of IL-6 and VEGF synthesis might be inter-related in rat kidney.
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