Published online before print May 27, 2003, doi: 10.1161/01.HYP.0000075082.06183.4E
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(Hypertension. 2003;42:31.)
© 2003 American Heart Association, Inc.
Scientific Contributions |
Imbalance of T-Cell Subsets in Angiotensin II–Infused Hypertensive Rats With Kidney Injury
From the Division of Nephrology and Endocrinology, University of Tokyo School of Medicine (J.S., M.N., K.Y., T.F.), Tokyo, and the Institute of Medical Sciences and Department of Internal Medicine, Tokai University School of Medicine (T.M., R.I., K.K.), Isehara, Kanagawa, Japan.
Correspondence to Dr Masaomi Nangaku, Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail mnangaku-tky{at}umin.ac.jp
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Abstract |
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Blockade of angiotensin (Ang) II is efficient in various renal diseases. Although interest has focused on the hemodynamic changes and reduction of proteinuria, recent studies emphasize the nonhemodynamic effects of Ang II on kidney injury. The aim of this study was to clarify the mechanisms of Ang II on the immune system that alter the balance of helper T-cell (Th) subsets. We used a continuous, Ang II infusion model of rats that develop hypertension, proteinuria, and tubulointerstitial damage, including de novo expression of
-smooth muscle actin and loss of endothelial cells. We isolated T cells from the spleen and measured cytokine levels by ELISA systems. Ang II–infused rats showed an increase in the Th1 cytokine 
-interferon and a decrease in the Th2 cytokine interleukin-4. The same change in cytokine mRNA expression in the spleen and kidney was confirmed by quantitative polymerase chain reaction analysis. Our ELISPOT assay showed an increase in the number of -interferon–secreting T cells by Ang II. To investigate whether these changes were specific effects of Ang II, we treated the model rats with the Ang II receptor blocker (ARB) olmesartan or the nonspecific vessel dilator hydralazine. Administration of the ARB ameliorated disease manifestations and the imbalance in Th subsets, whereas hydralazine did not, despite comparable effects on blood pressure. These results demonstrate a direct role of Ang II in the modification of Th balance. The imbalance of Th subsets was associated with hypertensive kidney injury induced by Ang II. Some of the beneficial effects of ARBs might be explained by their immunomodulatory reactions.
Key Words: angiotensin • angiotensin II type 1 receptor blocker • helper T cell • tubulointerstitial damage • cytokines
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Introduction |
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The renin-angiotensin system has been a target for research on hypertension for a long time. This system plays a crucial role in regulating a variety of renal functions, such as blood pressure (BP) and electrolyte and water homeostasis.1 Disorders of this system contribute importantly to the pathophysiology of hypertension, renal disease, and congestive heart failure.2 Most of the cellular and phenotypic changes induced by angiotensin (Ang) II are mediated by the angiotensin II type 1 (AT1) receptor, which is the principal Ang II receptor in the kidney.3,4 The ability of Ang II to influence BP and ion transport and to serve as a growth factor occurs largely through the AT1 receptor.5 Blockade of this receptor is efficient in a variety of renal diseases.6,7 Beyond its beneficial effects on hemodynamic changes and improvement of glomerular barrier function, recognition of its protective effects in several immune system–mediated diseases, such as myocarditis, chronic allograft rejection, and antiglomerular basement membrane nephritis, has recently increased.8–13 Although these findings of immune system modulation by Ang II are largely indirect, AT1 receptors have been suggested to exist in macrophages and T cells.14 Recent research by Nataraj et al15 indicates that the renin-angiotensin system regulates cellular immune responses acting through AT1 receptors by utilizing a calcineurin-dependent pathway, indicating direct effects of Ang II on T-cell biology.
Activated T cells can directly mediate a variety of diseases including renal injury, such as interstitial nephritis, glomerulonephritis, and glomerular crescents.16–19 A common paradigm in understanding the pathogenic T-cell responses is based on the notion that the helper T- (Th) cell response can be divided into those cells that predominantly secrete interleukin-2 (IL-2) and -interferon (-IFN) (Th1 cells) and those that predominantly secrete IL-4 and IL-10 (Th2 cells).20,21 In previous in vitro studies, Fernandez-Castelo et al22 reported a Th1 predominance in human lymphocytes stimulated by Ang II. We therefore decided to investigate whether the balance of T-cell subsets in vivo would be modified by Ang II and how an Ang II receptor blocker (ARB) would affect the imbalance in Ang II–induced renal disease.
In the present study, to clarify this hypothesis, we investigated Th balance in Ang II–infused hypertensive rats with kidney injury. These rats developed hypertension, proteinuria, and tubulointerstitial (TI) damage, including de novo expression of -smooth muscle actin (-SMA).23,24 Furthermore, we discovered that the Th1 cytokine -IFN was increased and that the Th2 cytokine IL-4 was decreased in this model of renal disease. Administration of olmesartan, an ARB, markedly ameliorated the manifestations of the disease and reversed the imbalance of Th subsets. To our knowledge, this is the first study to show the effects of Ang II on Th balance in vivo. Our novel findings suggest that imbalance in T-cell subsets might participate in the pathogenesis of Ang II–mediated renal injury.
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Methods |
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All animal studies conformed to the Animal Experimentation Guidelines at the University of Tokyo. Forty male, 6-week-old Wistar rats were studied in 5 groups (n=8 each). These included group III, which were Ang II–infused rats (infusion of Ang II, Wako; 435 ng · kg-1 · min-1) dissolved in Ringer’s lactate (Otsuka) for 2 weeks through subcutaneous osmotic minipumps (Durect)23,25; Ang II–infused rats that were administered a high dose (10 mg · kg-1 · d-1; group I) or a low dose (1 mg · kg-1 · d-1; group II) of olmesartan (Sankyo); Ang II–infused rats that were given hydralazine (15 mg · kg-1 · d-1, Sigma; group IV)26; and noninfused rats (group V). Seven and 14 days after infusion, systolic BP, blood urea nitrogen (BUN), and proteinuria measurements were made, and respective survival and sacrificial biopsies were performed. All surgical procedures were practiced under ether anesthesia.
On day 14, spleens were processed (Collector tissue sieves; Cosmobio). T cells isolated from splenocytes by a nylon fiber column T (Wako) were thawed in RPMI-1640 (Nissui); supplemented with fetal bovine serum, 2-mercaptoethanol, and human serum (Wako); and given a stimulation mixture, as previously described.27,28 Cells (2x106/well) were plated in 24-well culture clusters. Additionally, T cells from group V (n=3) were treated as group a (stimulated with 1 µmol/L Ang II),29 group b (stimulated with 1 µmol/L Ang II and 1 µmol/L olmesartan ),30 group c (stimulated with 0.03 µmol/L phorbol-12 myristate-13-acetate as a positive control), and group d (negative control, without any drugs in the medium). Cells were cultured in triplicate at 37°C in 5% CO2/95% air for 48 hours. Supernatants were collected for the cytokine quantification with ELISA kits (AN'ALYZA rat IFN- and IL-4 Immunoassays, Techne).
Real-time polymerase chain reaction (PCR) for rat splenocytes and kidneys was performed on an iCycler (Bio-Rad) after extraction of total RNA and reverse transcription. Commercially available reagent kits (PreDeveloped TaqMan assay reagent target kits, PE Biosystems) were used to detect the sequences of -IFN and IL-4 in cDNA samples according to the manufacturer’s protocol. All reactions were performed in triplicate. The amount of amplified molecules was given by 2-
Ct (Ct, or threshold cycle, represented for relative quantification of the input target number).31
We performed enzyme-linked immunospot (ELISPOT) experiments by using a rat IFN- ELISPOT kit (Techne). Freshly isolated T cells from the spleens of Ang II–infused, olmesartan-treated (group I), Ang II–infused (group III), and noninfused (group V) rats were plated at 2x106 cells/well in triplicate into the ELISPOT plate and stimulated by addition of the stimulation mixture, as mentioned previously for the ELISA method, under the same culture conditions for 48 hours. The blue spots corresponding to -IFN–secreting T cells were enumerated in a blinded fashion while being viewed under a dissection microscope.32,33
Kidney tissues for histologic analysis were prepared as previously described34 and stained with an indirect avidin-biotin immunoperoxidase method,35 with the following specific, primary antibodies: anti–-actin (Boehringer Mannheim),23 JG-12 (MedSystems Diagnostics),34 and ED-1 (Chemicon).25 Cryosections were used to stain T lymphocytes by OX-35 and G28 (BD Biosciences). Color was developed with diaminobenzidine. A semiquantitative scoring system evaluated TI injury as described previously.36 ED-1+ and CD4+/CD8+ cells in each TI tuft were enumerated. Quantification of 30 random TI tufts was performed in a blinded fashion.
Data are reported as mean±SD. Statistical comparisons were analyzed by the program StatView (Abacus Concepts) with ANOVA, followed by the Bonferroni/Dunn method for multiple-group comparisons. Nonparametric data were analyzed with the Kruskal-Wallis test. P<0.05 was considered statistically significant.
An expanded Methods section can be found in an online supplement available at http://www.hypertensionaha.org.
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Results |
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Systolic BP
All of the rats studied had a normal BP at the beginning of the study. BP rose markedly with Ang II infusion. The systolic BP of Ang II–infused rats remained high throughout the experimental course. As an antihypertensive reagent, we used olmesartan, which is an ARB. As a control antihypertensive reagent, we used hydralazine, a nonspecific vessel dilator. Hydralazine, low-dose olmesartan, and high-dose olmesartan significantly decreased systolic BP on days 7 and 14. Whereas BP levels in the high-dose olmesartan–treated group (group I) were lower than those in low-dose olmesartan (group II) or hydralazine (group IV) groups, the difference between group I and group IV did not reach statistical significance (Table 1).
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Urinary Protein Excretion and Renal Function
Ang II–infused rats demonstrated proteinuria on days 7 and 14. In rats given low-dose olmesartan or hydralazine, urinary protein excretion values were numerically lower, though not statistically different, from those of Ang II–infused rats (group III). In contrast, high-dose olmesartan had a remarkable antiproteinuric effect (Table 1). Ang II infusion induced a slight increase in BUN levels. All of the antihypertensive treatments reversed the exacerbation of renal function, but high-dose olmesartan was the most effective (Table 1).
Cytokine Levels Altered by Ang II Induction
To study the effect of Ang II infusion on Th balance, we measured -IFN as a representative Th1 cytokine and IL-4 as a representative Th2 cytokine in the culture media of T cells isolated from splenocytes. In Ang II–infused rats, we found an increase of -IFN (group III, 132.8±47.6 pg/mL vs normal control group V, 31.8±11.1 pg/mL; P<0.05) and a decrease of IL-4 (group III, 17.2±4.5 pg/mL vs normal control group V, 75.5±9.3 pg/mL; P<0.05). This imbalance of T-cell subsets was reversed by administration of the ARB olmesartan in a dose-dependent manner (-IFN: Ang II+high-dose olmesartan, group I, 34.5±2.1 pg/mL; Ang II+low-dose olmesartan, group II, 61.2±6.7 pg/mL, vs Ang II only, group III, P<0.05; IL-4: Ang II+high-dose olmesartan, group I, 74.4±4.5 pg/mL vs Ang II+low-dose olmesartan, group II, 26.7±5.1 pg/mL, and Ang II only, group III, P<0.05). Administration of hydralazine did not affect the imbalance of T-cell subsets induced by Ang II (-IFN: Ang II+hydralazine, group IV, 96.9±28.6 pg/mL vs Ang II only, group III, P=0.12; IL-4: Ang II+hydralazine, group IV, 18.3±1.3 pg/mL vs Ang II only, group III, P=0.81; Figure 1A).
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In an additional experiment, when cultured T cells were stimulated with Ang II, -IFN concentration was also increased (Ang II, group a, 46.5±1.8 pg/mL vs negative control, group d, 35.4±0.3 pg/mL; P<0.001), and IL-4 concentration was decreased (Ang II, group a, 6.8±0.2 pg/mL vs negative control, group d, 11.6±0.4 pg/mL; P<0.001). The effect of Ang II was significantly blocked by olmesartan (-IFN: Ang II+olmesartan group b, 36.4±1.0 pg/mL, P<0.001 vs group a; IL-4: Ang II+olmesartan group b, 10.5±0.2 pg/mL, P<0.001 vs group a; Figure 1B).
Real-Time Quantitative PCR Analysis
To confirm the cytokine data from the ELISA studies, we analyzed by real-time PCR the expression of genes of these cytokines in the spleens and kidneys from experimental animals. All of the assays were done in triplicate. The variance between triplicates was <5%. Quantitative PCR analysis of the spleen confirmed the ELISA results of imbalance of T-cell subsets induced by Ang II (-IFN increased: group III 16.35±0.2 vs normal control group V, 1.0±0.0, P<0.01; and IL-4 decreased: group III 0.16±0.014 vs normal control group V, 1.0±0.0; P<0.01). This imbalance was ameliorated by treatment with the ARB in a dose-dependent manner (-IFN: Ang II+high-dose olmesartan, group I, 1.4±0.1 vs Ang II+low-dose olmesartan, group II, 10.2±0.4 vs Ang II only group III, P<0.01; and IL-4: Ang II+high-dose olmesartan, group I, 0.9±0.04 vs Ang II+low-dose olmesartan, group II, 0.4±0.01 vs Ang II only group III, P<0.01). We did not observe any effects of hydralazine on the imbalance of T-cell subsets induced by Ang II (-IFN: Ang II+hydralazine, group IV, 15.9±0.2 vs Ang II only group III, P=0.07; and IL-4: Ang II+hydralazine, group IV, 0.2±0.01 vs Ang II only group III, P=0.16; Figure 2).
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In the kidneys, the same modification of the cytokine profile induced by Ang II could also be observed. -IFN was increased and IL-4 was decreased in Ang II–infused rats compared with normal controls. High-dose olmesartan drastically ameliorated the imbalance of T-cell subsets, whereas low-dose olmesartan and hydralazine had less or no effect on the imbalance (data not shown).
Evaluation of Cytokine-Producing T Cells
The number of cytokine-producing T cells was evaluated by ELISPOT assay. Ang II induction led to a 2-fold increase in the number of -IFN–secreting T cells compared with noninfused rats (109.7±3.7/well, group III vs 49.0±0.4/well, group V; P<0.001). Olmesartan treatment dramatically abolished this modification to a normal level (51.7±3.7/well, group I vs group III; P<0.001; Figure 3).
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TI Injury in Ang II–Infused Rats
To study whether improvement of the imbalance of T-cell subsets was accompanied by amelioration of disease manifestations, we performed a detailed analysis of the kidneys of the experimental animals. The glomeruli largely appeared normal in Ang II–infused rats as well as in normal control rats, although a few of them showed occasional, focal, segmental hyalinosis. In contrast, the principal histologic finding was the TI damage induced by Ang II. Light microscopy showed frequent areas of tubular dilation and atrophy, with evident formation of tubular casts. Mononuclear cell infiltration as well as widening and fibrosis were easily seen in some interstitial spaces. These lesions were dramatically abolished by administration of high-dose olmesartan, and the effect of amelioration of the TI damage was less or none in rats treated with low-dose olmesartan or hydralazine (Table 2 and Figures 4a through 4e).
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-SMA marks smooth muscle cells, activated mesangial cells, and myofibroblasts.23 The immunostaining of -SMA serves as a sensitive marker for injured tubulointerstitium. The infusion of Ang II was also associated with de novo expression of -SMA by interstitial fibroblasts. These "myofibroblast-like" cells frequently surrounded dilated and damaged tubules. The immunostaining of -SMA appeared positive on day 7 and became more intense and diffuse at the end of Ang II infusion. The expression was decreased in rats treated with olmesartan, and high-dose olmesartan abolished de novo expression of -SMA, indicating marked amelioration of TI injury in this group of rats. Staining of -SMA in Ang II+hydralazine–treated rats was not statistically different from that of the Ang II–infused rats (Table 2 and Figures 4f through 4j). TI injury was further evaluated by loss of peritubular capillaries, as assessed by JG-12 staining. The loss of peritubular capillaries was prevented in rats receiving olmesartan but not hydralazine (Table 2 and Figures 5a through 5e).
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ED-1 staining revealed monocyte/macrophage infiltration.25 An important finding was that macrophage infiltration, which is a manifestation of Th1 predominance, was in parallel with the imbalance of T-cell subsets. With stimulation by Ang II for 2 weeks, TI injury was associated with local infiltration of macrophages. The infiltration was reduced by high-dose olmesartan. Low-dose olmesartan or hydralazine did not affect macrophage infiltration (Table 2 and Figures 5f through 5j).
T cells play a critical role in this study. A recruitment of T cells in TI of the kidney, as documented by CD4 and CD8 staining, could be observed in Ang II–infused rats. When infused rats were treated with high-dose olmesartan, T-cell infiltration was absent. Low-dose olmesartan and hydralazine had little effect on T-cell infiltration (Table 2).
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Discussion |
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In this study, we examined a model of Ang II–mediated, hypertensive TI injury,23 with an emphasis on the effects of Ang II on the imbalance of Th cell subsets. The direct effects of Ang II on the immune system have been the focus of recent studies,8–15 and previous in vitro studies, which demonstrated a Th1 predominance in human blood lymphocytes induced by Ang II,22 impelled us to clarify in vivo the cytokine profile in this model.
Th cells differentiate into 2 distinct subpopulations, each producing its own panel of cytokines and mediating separate functions. Based on their cytokine secretion profile, Th cells are functionally subdivided into Th1 and Th2 cells. Th1 cells secrete -IFN, IL-2, and tumor necrosis factor-ß, thereby activating macrophages and inducing delayed-type hypersensitivity responses. In contrast, Th2 cells produce IL-4 and some other interleukins, providing B-cell help and suppressing cell-mediated immunity.37 The cytokines themselves keep in balance, often under the control of a genetic predisposition: Th1 cells inhibit the production of Th2 cells, whereas Th2 cells prevent the production of Th1 cells.38 Factors leading to differentiation into 1 subtype or the other are being avidly investigated. In our study, we demonstrated a significant increase in a Th1 cytokine, -IFN, and a decrease in a Th2 cytokine, IL-4, in Ang II-infused rats. Both the ELISA method and quantitative PCR analysis confirmed the results of imbalance of Th-cell subsets in this model. To our knowledge, this is the first study to demonstrate the direct effects of Ang II as a modulator of Th balance.
It is well known that mononuclear phagocytes, including macrophages, play a central role in inflammatory diseases. This function can be directly regulated by the immune system, such as T cells.39 Participation of T lymphocytes and macrophages was the prominent feature in this study. Macrophages are induced and activated by a Th1 cytokine, -IFN,40 mediating tissue destruction. In our study, Ang II–infused rats showed, mononuclear cell infiltration, documented by immunostaining with ED-1 (Table 2 and Figure 5) and evident infiltration of CD4+ and CD8+ T cells at the sites of TI injury, documented by immunostaining with OX-35 and G28 (see Table 2), in good correlation with the increase in -IFN. Furthermore, infiltration of macrophages and T lymphocytes was inhibited by blockade of the AT1 receptor in parallel with the restoration of T-cell balance. Hisada et al13 previously demonstrated a direct effect of Ang II on the infiltration of macrophages, which was induced by monocyte chemoattractant protein-1 expression in an immunologically mediated renal-injury model of anti-glomerular basement membrane (GBM) nephritis in mice. Although elucidation of the mechanism of the Ang II–macrophage feedback loop is beyond the scope of this study, our result of monocyte/macrophage infiltration associated with -IFN increase in Ang II–induced TI injury suggests participation of the Ang II–Th1-macrophage cascade in this model.
To determine whether the imbalance of Th subsets in this model was specifically induced by Ang II via the AT1 receptor, we used olmesartan, an ARB. In this study, high-dose olmesartan dramatically ameliorated the manifestations of TI damage induced by Ang II. Improvement of the morphological changes in the tubulointerstitium was associated with complete abolishment of a phenotypic change of interstitial fibroblasts, in which they expresses contractile (-SMA) proteins.25 Markers reflecting the severity of TI disease, such as peritubular capillary loss by JG-12 staining, were also reduced by treatment with high-dose olmesartan. Although amelioration of the manifestations of disease was evident in the olmesartan-treated group, hydralazine did not modify proteinuria or other manifestations of TI disease, despite its comparable BP-lowering effects, suggesting that the mechanism of amelioration of disease by ARBs is, at least partly, Ang II specific and BP independent.
Some groups have concluded that uremia per se is a cause of some derangements of the immune system, such as T-cell function and cytokine production,41 and could induce a bias of differentiation toward the Th1-type cells42; therefore, infection in the uremic state was easily predisposed by the immune deficit. However, other groups have proposed that the immune responsiveness of the uremic host is normal43 and that the alterations of cytokines were due to the effect of treatment of terminal uremia.44 In the current study, Ang II infusion caused only a small alteration in renal function. This model of the rat was not uremic, as documented by the BUN level, which was below the moderate range of uremia43; even more, in our study T-cell proliferation was increased but not reduced or unchanged, which is often observed in uremic states45,46; thus, the possibility that uremia might secondarily result in an alteration in systemic immunity could be ruled out.
We observed that the imbalance of Th subsets in Ang II–infused rats was amended by olmesartan. It remains to be determined whether the regulation of Th balance by Ang II is direct or is mediated by some other cells, such as dendritic cells.47,48 However, in our study, a direct, stimulating effect of Ang II on cytokine production in cultured T lymphocytes has been demonstrated, and olmesartan markedly blocked the action of Ang II (Figure 1B). Many previous studies have shown that the AT1 receptor is the predominant Ang II receptor expressed by immune cells in the spleen.15 Tsutsumi and associates49 subsequently demonstrated large numbers of binding sites for Ang II in the rat spleen and found that these sites were primarily AT1 receptors. Coffman’s group (Nataraj et al15) also demonstrated that AT1a receptors were expressed in a variety of splenocyte populations, including T cells, macrophages, and B cells. Thus, it is not surprising that Ang II has direct actions on T cells in rats and that an ARB is able to block this effect. Ang II might act as a shift in the transformation of T cells from "naïve" to "activated" during the course of disease.29 In our study, the number of -IFN–secreting T cells documented by ELISPOT assessment was markedly increased (Figure 3), consistent with the local infiltration of CD4+ and CD8+ T cells. We certainly favor the view that Ang II activated T cells directly, thus releasing pathogenic Th1 cytokines like -IFN and resulting in end-organ damage. The expression profiles of -IFN and IL-4 returned to normal when the animals were treated with olmesartan, confirming that modification of the cytokine profile induced by Ang II was mediated by the AT1 receptor. These findings strongly assert that Ang II plays a direct role in the pathogenesis of hypertensive TI injury. This novel in vivo result promulgates for the first time the concept that Ang II–induced renal TI injury occurred in conjunction with a Th1-like cytokine profile.
Perspectives
In this study, whether Ang II affected the balance of Th first, thereby causing the disease manifestations, or that Ang II itself brought about the renal injury via other mediators, with an imbalance of Th subsets as an epiphenomenon, cannot be distinguished. Further studies are in progress to address this issue. Our present in vivo findings provide novel insights into a direct role of Ang II in the modification of T-cell balance. The imbalance of Th cell subsets was associated with hypertensive kidney injury induced by continuous Ang II administration. Some of the beneficial effects of ARBs might be explained by their immunomodulatory reactions. However, our observations have been made in a rat model of Ang II infusion, and we cannot therefore extrapolate directly our results to humans. The more detailed mechanisms of Ang II within the immune system and the role of ARBs in the imbalance of T-cell subsets in humans should be addressed. We hope that our studies might lead to new strategies to treat hypertensive patients with kidney injury.
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Acknowledgments |
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This study was supported by grants from the Japanese Ministry of Health, Labor and Welfare and from the Sankyo Pharmaceutical Co.
Received October 21, 2002; first decision November 13, 2002; accepted April 23, 2003.
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