Angiotensin II down-regulates the SR-BI HDL receptor in proximal tubular cells
1 Department of Medicine, University of Jena and 2 Department of Medicine, University of Hamburg, Hamburg, Germany
Correspondence and offprint requests to: Gunter Wolf, MD, Klinik für Innere Medizin III, University of Jena, Erlanger Allee 101, D-007347 Jena, Germany. Email: gwolf{at}med.uni-jena.de
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Abstract |
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Background. The kidney plays an important role in the metabolism of lipoproteins, but renal cells are also a target of lipids under pathophysiological conditions contributing to organ damage and progression of disease. The majority of studies has focused on the interaction of renal cells with low-density lipoproteins. Relatively little is known of potential metabolism of high-density lipoproteins (HDL) on renal cells However, diverse pathophysiological situations, such as the nephrotic syndrome and acute renal injury, may be associated with an activated renin–angiotensin system as well as altered renal handling of HDL. Therefore, the present study sought to gain insight into the expression of the HDL receptor scavenger receptor class B type I (SR-BI) in cultured renal cells and a potential regulation by angiotensin II (ANG II).
Methods. Different renal cells lines and primary cultures (proximal tubular and mesangial cells) were screened by western blot for the expression of SR-BI. MCT cells, a mouse proximal tubular cell line, were selected for further studies. SR-BI protein and mRNA expression were determined after treatment with various doses of ANG II in the presence or absence of AT1- or AT2-receptor blocker. Uptake of HDL-associated cholesteryl ester into MCT cells was determined. Finally, rats were infused intraperitoneally with ANG II for 3–7 days, proximal tubules were isolated by differential centrifugation and SR-BI protein expression was assessed.
Results. SR-BI protein was expressed in various primary cultures and permanent renal cell lines. ANG II (10–10–10–6 M) treatment for 24 h induced a significant down-regulation of SR-BI protein and mRNA expression in MCT cells. This suppression was attenuated by an AT1-receptor antagonist whereas an AT2-blocker was without effect. MCT cells revealed a high selective uptake of HDL cholesteryl ester that was significantly higher than that in syngeneic mesangial cells. ANG II for 24 h significantly reduced this selective HDL cholesteryl ester uptake into MCT, but not mesangial cells. Finally, ANG II- infusion into rats for 3 and 7 days induced a significant decrease of SR-BI protein expression in isolated tubules.
Conclusions. Our data show that ANG II mediates down-regulation of SR-BI expression on proximal tubular cells in vivo and in vitro. However, the effects were small and additional experiments are necessary to confirm these first observations. The attenuated SR-BI expression is functionally relevant and associated with a decrease in cholesteryl ester uptake. ANG II-mediated suppression may contribute to various pathophysiological situations, such as acute tubular injury, the nephrotic syndrome and atherosclerosis.
Keywords: cholesterol transport; high-density lipoproteins; lipid metabolism; renin–angiotensin system; selective uptake; SR-BI
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Introduction |
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The kidney plays an important role in the metabolism of lipoproteins. For example, lipoprotein(a) is metabolized there and apolipoproteinA-I fragments are excreted into the urine [1]. On the other hand, renal cells are also a target of lipoproteins and lipoprotein-mediated injury can contribute to the progression of various renal diseases [2]. The majority of these studies addressed the role of naïve or modified low-density lipoproteins (LDL) [2,3]. In contrast, only little is known of renal handling of high-density lipoproteins (HDL). Recently, Zager and co-workers [4] reported that acute renal injury causes accumulation of free and esterified cholesterol in proximal tubules. Since changes in renal handling of HDL have been found in pathophysiological changes with an activated renin–angiotensin system (e.g. nephrotic syndrome, acute renal failure and septicaemia), we were interested whether cultured proximal tubules expressed scavenger receptor BI (SR-BI), a cell surface receptor that binds HDL and mediates selective uptake of cholesteryl esters [5], and whether angiotensin II (ANG II) influences SR-BI expression.
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Subjects and methods |
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Cell culture
For an initial screening of SR-BI expression, the following cultured cells were used: MCT cells (a mouse proximal tubular cell line derived from SJL mice [6]), MMC (a mouse mesangial cell line from SJL mice [7]), TFB (a renal fibroblast cell line from SJL mice [7]), LLC-PK1 (a porcine tubular cell line with some properties of proximal tubules), PC 12 cells (a rat adrenal pheochromocytoma cell line [8]) and Y1-BS1 cells (a murine adrenocortical tumour cell line with high SR-BI expression that served as a positive control [9]). In addition, primary cultures of murine proximal tubular and mesangial cells were isolated from C57/black mice as described previously [10]. All cells were grown in Dulbecco's modified Eagle's medium (DMEM; Gibco-BRL, Eggenstein, Germany) with 10% fetal calf serum (FCS) in 5% CO2 at 37°C. Cells were passaged as appropriate for the particular cell line.
Western blots
MCT cells were stimulated with various concentrations of ANG II (10–10–10–6 M; Sigma, Deisenhofen, Germany). Some cells were also treated with the AT1-receptor antagonist losartan (10–6 M; gift from MSD, Munich, Germany) or the AT2-receptor blocker PD123177 (10–6 M; Sigma). After washing in ice-cold phosphate-buffered saline (PBS), cells were lysed directly on ice in 150 µl of a buffer containing 2% sodium dodecyl sulphate (SDS) and 60 mmol/l Tris–HCl (pH 6.8) supplemented with a cocktail of protease inhibitors (CompleteTM; Boehringer Mannheim, Germany; contains antipain–HCl, chymostatin, leupeptin, bestatin, pepstatin, phosphoramidon, aprotinin, EDTA). The protein content was measured by a modification of the Lowry method. Protein concentrations were adjusted to 70 µg/sample and 5% glycerol/0.03% bromophenol blue/10 mmol/l dithiothreitol were added, then samples were boiled for 5 min. Proteins were separated under denaturing conditions on a 7% NuPAGETM pre-cast gel (Invitrogen, Karlsruhe, Germany). High molecular weight markers (Rainbow markers; Amersham, Braunschweig, Germany), which comprise 45 000–200 000 Da, served as the molecular weight standards. After completion of electrophoresis, proteins were electroblotted onto a nitrocellulose membrane (High-bond-N; Amersham) in transfer buffer (50 mmol/l Tris–HCl, pH 7.0, 380 mmol/l glycine, 0.1% SDS, 20% methanol). Filters were stained with Ponceau S to control for equal loading and transfer. The blots were blocked in 5% non-fat dry milk in PBS with 0.1% Tween-20 for 1 h at 22°C. For the detection of SR-BI, a 1:100 dilution of a rabbit polyclonal antibody was used (Novus Biologicals, Littleton, CO, USA). This antibody was generated against a GST-fusion protein containing amino acid residues 496–509 of mouse SR-BI coupled to KLH. Washes, incubations with horseradish peroxidase-conjugated anti-rabbit secondary antibodies and detection using the ECL reagent (Amersham) were performed according to the manufacturer's recommendations. To control for small variations in protein loading and transfer, membranes were washed for 30 min in PBS with 0.1% Tween-20 and were reincubated with a mouse monoclonal antibody against ß-actin (1:2000 dilution; Sigma). Exposed films were scanned with Fluor-STM multi-imager (Bio-Rad Laboratories, Hercules, USA) and data were analysed with the computer program Multi-AnalystTM from Bio-Rad. Signal intensities of SR-BI were normalized to ß-actin and intensity of the bands from control cells (no ANG II) was assigned an arbitrary value of 1.0.
Northern blots
MCT cells were stimulated as appropriate. After washing in RNase-free PBS, cells were directly lysed with acid guanidinium thiocyanate and total RNA was isolated. Equal amounts of total RNA (15 µg per lane) were denatured in formamide–formaldehyde at 65°C and electrophoresed through a 1.2% agarose gel containing 2.2 M formaldehyde. Blotting, hybridization and washing conditions were exactly as described previously [10]. A 0.7 kb cDNA fragment encoding murine SR-BI was used [5]. For control hybridizations, a 2.0 kb cDNA insert of the plasmid pMCI encoding the murine ribosomal 18 S band was applied. Northern blots were repeated three times with qualitatively similar results.
Uptake of doubly radiolabelled HDL3
Human HDL3 (d: 1.125–1.21 g/ml) was isolated by ultracentrifugation from pooled plasma of healthy donors. Doubly radiolabelled HDL3 was prepared as described previously with 125I-N-methyl tyramine cellobiose (125I-NMTC) for the protein part of HDL3 and 3H-cholesteryl oleyl ether (3H-CET; Amersham) to trace the HDL3-associated cholesteryl ester [9]. LLC-PK1, MCT and MMC cells were reincubated for 24 h in DMEM without FCS supplemented with 5 mg/ml bovine serum albumin (Sigma) in the presence or absence of 10–7 M ANG II. Uptake of HDL3 tracers was then initiated by incubation of cells with the doubly radiolabelled HDL3 (10 µg HDL3 protein per ml) for 4 h at 37°C. After this incubation period, the medium was aspirated, taking care not to remove attached cells, and cells were washed three times with PBS. Cells were dissolved in 0.1 N NaOH, protein content was measured by a modification of the Lowry method and 125I was determined in a gamma counter whereas 3H was measured by liquid scintillation spectrometry after lipid extraction. HDL3 selective uptake of cholesteryl ester was calculated as described previously [9].
Animal experiments
To test a potential role of ANG II on tubular SR-BI expression in vivo, male Wistar rats (body weight 200 g) were intraperitoneally infused with ANG II at a rate of 250 ng/min using osmotic minipumps (Alzet 2002, infusion rate 0.5 µl/h; for details see [11]). Control animals were infused with PBS. Animals were either infused for 3 or 7 days with ANG II. Systolic blood pressure was measured on awake, slightly restrained animals on days 2 and 6 using tail plethysmography. At the end of the infusion period, animals were slightly anaesthetized with ether and the kidneys were perfused in situ via the aorta first with 20 ml ice-cold PBS, followed by perfusion with 20 ml ice-cold collagenase IIN (253 U/mg; Biochrome, Berlin, Germany) redissolved at 1 mg/ml in DMEM medium. Tubules were isolated by differential centrifugation using a Percoll (Pharmacia, Freiburg, Germany) gradient as described previously [10]. The two bands near the cushion interface in the 45% iso-osmotic Percoll (d: 1.02 g/ml) that contained long proximal tubules were removed and pooled. All preparations were performed on ice. The final tubular preparation had a purity of 90%, as judged by light microscopy. Tubular preparations from three rats were pooled, lysed in 150 µl of a buffer containing 2% SDS and 60 mmol/l Tris–HCl (pH 6.8) supplemented with a cocktail of protease inhibitors (CompleteTM) and equal amounts of proteins were subjected to electrophoresis and western blotting to determine SR-BI protein expression. The whole experiment (animal infusion, tubular preparation and western blotting) was repeated three times with three rats in each individual group for the 7 day experiment and with three rats for the 3 day infusion period.
Statistical analysis
All data are presented as means±SEM. Statistical significance between different groups was first tested with the non-parametric Kruskal–Wallis test. Individual groups were tested subsequently using the Wilcoxon–Mann–Whitney test. A P-value of <0.05 was considered significant.
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Results |
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Expression of SR-BI in cultured renal cells
To gain insight into the expression of SR-BI in vitro, several renal cells were screened by western blot analysis. The used antibody detected a 82 kDa band, being typical for SR-BI [5]. As shown in Figure 1, proximal tubular cell lines from different species (MCT, LLC-PK1) as well as mouse primary cultures of proximal tubular cells expressed SR-BI. In addition, this HDL receptor was also expressed in mouse mesangial cells (MMC, two primary isolates) and a renal fibroblast cell line (TFB). PC 12 rat pheochromocytoma cells failed to express SR-BI (Figure 1). However, compared with Y1-BS1 adrenocortical tumour cells that served as a positive control, SR-BI expression was much lower in renal cells (Figure 1).
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Effect of ANG II on SR-BI expression in MCT cells
Different concentrations of ANG II (10–9–10–7 M) for 24 h induced a significant down-regulation of SR-BI protein expression in MCT cells (Figure 2). ANG II also suppressed SR-BI mRNA expression (Figure 3). The ANG II-mediated down-regulation of SR-BI protein and mRNA expression was transduced through AT1-receptors, because the AT1-receptor antagonist losartan, but not PD 123177 (an AT2-receptor blocker), attenuated this response (Figures 4A and 4B).
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Effect of ANG II on selective HDL3-uptake
Selective uptake of HDL3-associated cholesteryl esters was measured to further test whether down-regulation of SR-BI receptors is associated with functional consequences, compared with values reported in the literature for Y1-BS1 known to exhibit a high SR-B1 expression [5], MCT revealed a robust selective uptake of cholesteryl esters from HDL3 whereas the transport was lower in syngeneic MMC cells (Figure 5). Pre-incubation of MCT cells, but not of MMC cells, for 24 h with 10–7 M ANG II significantly reduced selective cholesteryl esters uptake from HDL3 (Figure 5).
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Infusion of ANG II into rats
To investigate whether an ANG II-mediated suppression of SR-BI on tubular cells is also operative in vivo, rats were intraperitoneally infused with ANG II using osmotic minipumps. Systolic blood pressure was significantly increased 2 and 6 days after ANG II infusion compared with controls (controls: 110±5 mmHg; ANG II-infusion for 2 days: 156±12, P < 0.05; ANG II-infusion for 6 days: 220±10 mmHg, P < 0.01; n = 3–9). As demonstrated in Figure 6, isolated proximal tubules from ANG II-infused rats after 3 and 7 days exhibited significantly reduced SR-BI protein expression compared with controls (controls: 1.00; ANG II-infusion for 3 days: 0.75±0.05, P < 0.01; ANG II-infusion for 7 days: 0.71±0.01, P < 0.01; relative expression of SR-BI normalized to ß-actin; n = 3).
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Discussion |
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The present study provides evidence that SR-BI, the specific receptor for HDL, is expressed on proximal tubular cells and ANG II leads to a down-regulation in vitro and in vivo. Although the expression of SR-BI on proximal tubular cells was reported previously in the landmark study by Zager et al. [4], a regulation by ANG II was not known. This effect is mediated through AT1-receptors and is functionally relevant, because selective uptake of HDL3-associated cholesteryl esters is reduced in tubular cells pre-treated with ANG II. Since we have shown previously that ANG II fails to induce apoptosis in MCT cells, suppression of SR-BI and attenuated cholesteryl ester uptake is unlikely caused by unspecific toxic effects.
The overall effect of ANG II-mediated suppression is rather small and additional work is needed to establish more firmly the observed ANG II effects. It could be certainly argued whether a reduction of SR-BI expression by 
25% appears biologically relevant. However, suppression of SR-BI expression after ANG II treatment was associated with a significantly reduced cholesteryl ester uptake into proximal tubular cells. This effect was specific and not observed in mesangial cells, despite these cells expressing AT1 receptors [7] and SR-BI. These findings provide a strong argument for the specificity of the effect.
We have not observed a strict dose-dependent correlation between ANG II levels and suppression of SR-BI. We have reported previously a Kd of 0.89 nM for ANG II receptors on MCT cells [6]. This would explain why already 10–10 M ANG II exerts a down-regulation of SR-BI protein. However, our study has limitations, because some of the effects were observed at rather supraphysiological ANG II concentrations.
Although it is difficult to compare the time frame between the in vitro and in vivo experiments, the suppression of SR-BI already after 3 days of infusion at a time-point when the blood pressure was modestly enhanced suggests that the down-regulation of the transporter is a rather early event. At this time-point, ANG II-infused rats had no histological signs of renal damage (data not shown). In addition, we have shown previously that the used dose of ANG II causes only relatively minor morphological changes even after 7 days [11]. Nevertheless, we could not exclude that other additional mechanisms may have contributed to the down-regulation of SR-BI after 7 days of ANG II infusion, but think that an unspecific effect, such as structural damage, is very unlikely to contribute to SR-BI suppression after 3 days of infusion. In this regard, it is not possible to separate the direct effect of ANG II from a hypertension-induced mechanism in this model.
It has been shown previously that SR-BI is the major receptor involved in selective uptake of cholesteryl esters from HDL by tissues [12]. SR-BI is expressed strongly on the surface of steroidogenic cells, such as in the cortical zone of the adrenal gland, ovary, Leydig cells of the testes and in the liver (for review see [13]). It is assumed that SR-BI expression in these tissues serves to provide cholesterol for steroid hormone synthesis [13]. In addition, SR-BI is expressed in lower abundance in many mammalian tissues, including brain, vasculature, adipocytes and macrophages [13]. Contrary to the LDL endocytotic pathway, in which LDL is internalized in clathrin-coated pits, SR-BI binds HDL and the core cholesteryl esters are delivered selectively to the cells without uptake of the complete lipoprotein. Furthermore, SR-BI is also involved in efflux of free cholesterol [13]. Binding of HDL to SR-BI initiates multiple signal transduction pathways, such as protein kinase C and mitogen-activated protein kinases [14].
What pathophysiological role for renal diseases may ANG II-mediated suppression of SR-BI on tubular cells play? It is obvious that further studies are necessary to convincingly answer this question, but a few intriguing suggestions could be made. The nephrotic syndrome is characterized by a marked elevation of plasma HDL concentration [15]. Although increased production of HDL clearly contributes to this effect, work by Kaysen and associates [15] demonstrated a decrease in HDL catabolism in experimentally induced nephrotic syndrome. Indeed, Liang and Vaziri [16] recently showed a down-regulation of SR-BI in the liver in rats with puromycin-induced nephrotic syndrome. Since renal ANG II levels are markedly elevated in the nephrotic syndrome and proteinuria further increases locally formed ANG II [17], it is possible that ANG II-mediated down-regulation of SR-BI on tubular cells contributes to high circulating HDL levels.
In a series of elegant experiments, Zager and co-workers [4,18,19] studied the role of cholesterol in proximal tubular injury in models of acute renal failure. They found that acute renal injury induces accumulation of free cholesterol in proximal tubular cells [4]. This stress-induced cholesterol increment may protect tubular cells from further injury, a phenomenon called ‘acquired cytoresistance’ [18]. Although tubular synthesis obviously contributes to this accumulation of cholesterol, Zager et al. [18] showed that tubular cells revealed a decrease in cholesterol efflux. Tubular expression of SR-BI was significantly reduced in acute renal tubular injury and likely contributed to cellular cholesterol overload by reducing efflux of free cholesterol from tubular cells into the blood [18,19]. The mechanisms of a reduction in SR-BI during tubular injury are not known, but ANG II could play a role in this process.
Experiments using genetically engineered mice either with overexpression or deletion of SR-BI have established clearly that SR-BI expression protects against atherosclerosis (for review see [13]). Diverse mechanisms, including generation of nitric oxide, stimulated reverse cholesterol transport and contribution to 
-tocopherol-mediated vascular protection, may contribute to the potential antiatherogenic activities of SR-BI [13]. Taking into account the well-established role of ANG II in the formation of atherosclerosis [20], it is possible that ANG II-mediated suppression of SR-BI could be involved in these effects.
In summary, tubular suppression of SR-BI through ANG II may contribute to changes in HDL processing by the kidney. Nevertheless, further experiments in various ANG II-dependent models of renal injury are necessary to confirm this first observation.
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Acknowledgments |
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This study was supported by the Deutsche Forschungsgemeinschaft (Wo 460/2–6, 2–7).
Conflict of interest statement. None declared.
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Accepted in revised form: 12. 1.05
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