(Hypertension. 1996;28:973-979.)
© 1996 American Heart Association, Inc.
Articles |
Experimental Studies on the Role of Intercellular Adhesion Molecule-1 and Lymphocyte Function–Associated Antigen-1 in Hypertensive Nephrosclerosis
the Department of Internal Medicine–Nephrology, University of Erlangen–Nurnberg (Germany).
Correspondence to Monika Mai, PhD, Department of Medicine IV, Loschgestraße 8½, W-91054 Erlangen, FRG.
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Abstract |
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T helper cells and macrophages infiltrate into the renal cortical interstitium during the course of hypertensive nephrosclerosis. To investigate the mechanisms of mononuclear cell infiltration, we examined the expression of the intercellular adhesion molecule-1 (ICAM-1) and its counterpart lymphocyte function–associated antigen-1 (LFA-1) in the progression of hypertensive renal injury. We studied nonclipped kidneys of two-kidney, one clip renovascular hypertensive and sham-operated control rats immunohistochemically at 4, 7, 14, and 28 days after clipping (n=5 per group and time point). Systolic pressure was significantly elevated by day 7 (154±4 versus 117±6 mm Hg in sham, P<.05). The development of hypertension resulted in a progressive increase of ICAM-1 expression in the perivascular and interstitial areas of the renal cortex and on proximal tubular brush borders. Only a few glomeruli showed augmented ICAM-1 staining. Increased ICAM-1 was associated with an accumulation of LFA-1–positive mononuclear cells in the perivascular region (day 14: 15±4 versus 2±0.2 cells/mm2 in sham, P<.005) and intertubular region (127±11 versus 32±3 cells per millimeter squared in sham, P<.005). The maximum was obtained at day 14 and remained elevated until day 28. In addition, the number of interstitial LFA-1–positive infiltrating cells was related to the degree of interstitial and tubular ICAM-1 expression and correlated with blood pressure (r=.75, P<.001, n=18). Our data suggest that ICAM-1 is involved in the recruitment of macrophages/lymphocytes via specific interaction of ICAM-1 and LFA-1 in this model of hypertensive target-organ damage.
Key Words: hypertension, renovascular • leukocytes, mononuclear • lymphocyte function–associated antigen-1 • intercellular adhesion molecule-1
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Introduction |
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In a previous study,1 we showed that hypertensive nephrosclerosis is characterized by interstitial accumulation of the extracellular matrix components collagen types I, III, IV, V, and VI and fibronectin. These matrix changes were accompanied by a progressive infiltration of mononuclear cells in the cortical interstitium, suggesting that the macrophages and T lymphocytes contribute to the development of fibrogenesis.1 Similar findings were recently reported by Eng et al.2
Infiltrating mononuclear cells are important effectors of injury in allograft rejection, glomerulonephritis, and tubulointerstitial nephritis.3 4 5 Recruitment of infiltrating cells is mediated by a dynamic interaction of cell surface adhesion molecules expressed on resident tissue cells with cognate ligands on leukocytes.6 7 8 One of the most important interactions is between ICAM-1 and LFA-1. ICAM-1 plays a major role in the adhesion of macrophages and T lymphocytes to activated endothelium via binding to LFA-1 antigen.9 10 Moreover, ICAM-1 seems to play a role in directing the migration of leukocytes in experimental glomerulonephritis.11
Many studies have reported striking changes in ICAM-1 expression in inflammatory kidney diseases such as primary glomerulosclerosis,12 lupus nephritis,13 renal allograft rejection,14 and interstitial nephritis.15 The functional role of the interaction between ICAM-1 and LFA-1 in leukocyte recruitment in glomerulonephritis has recently been demonstrated by in vivo antibody blocking studies.16 17 Furthermore, the in vivo administration of monoclonal anti–ICAM-1 or anti–LFA-1 has a protective effect on ischemic acute renal failure.18 Few in vitro data exist concerning ICAM-1 and hypertension. Cerebrovascular endothelial cells from genetically hypertensive rats exhibited a greater sensitivity to cytokines and a higher level of ICAM-1 expression.19 Other leukocyte abnormalities have been described in genetically hypertensive rats, including elevated circulating leukocyte counts20 and decreased leukocyte adherence and emigration,21 probably caused by a defect in selectin-mediated leukocyte adhesion in these animals.22 However, these differences may be due to genetic differences between hypertensive and normotensive rat strains rather than to high BP.
The aim of this study was to investigate the ICAM-1/LFA-1 pathway in renal hypertensive injury. We used an inducible, nongenetic model of hypertension to exclude alterations in ICAM-1 or LFA-1 unrelated to high BP. We examined the localization and alterations of renal ICAM-1 expression and LFA-1–expressing cells early after the induction of hypertension.
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Animals
Male Sprague-Dawley rats were obtained from Charles River Wiga (Sulzfeld, Germany) and received standard chow (Altromin) and tap water.
Experimental Protocol
2K1C hypertension was induced when the rats weighed 150 to 180 g, as previously described.1 Briefly, a 0.20-mm-ID silver clip was placed around the left renal artery through a flank incision while the rats were under methohexital anesthesia. The right kidney remained untouched. Sham-operated control rats underwent a similar procedure, with manipulation of the left renal artery but without clip application.
Systolic arterial BP was measured by tail-cuff plethysmography with rats under light ether anesthesia. Measurements were performed blinded and weekly and additionally on the day when the rats were killed. Body weight was measured twice weekly. Rats that failed to thrive or gain weight were excluded because these phenomena may indicate the occurrence of malignant hypertension.23
The rats were anesthetized with methohexital and killed by exsanguination 4, 7, 14, and 28 days after clipping or sham operation (n=5 in each group). The hearts and nonclipped kidneys were immediately removed and weighed. The kidneys were bisected along their longitudinal axis for immunohistological examinations. All procedures done in rats were performed in accordance with the guidelines of the American Physiological Society and were approved by the local government's ethics committee.
Antibodies
Mouse monoclonal primary antibodies used in this study were as follows: ED1 (1:1000, Camon), an IgG to a rat cytoplasmic antigen present in macrophages, monocytes, and dendritic cells; W3/25 (1:2000, Camon), an anti-rat IgG to a surface CD4 antigen on T helper cells; 1A29 (1:500, Medac), purified IgG1 to rat ICAM-1 (CD54)24 ; and WT1 (1:250, Medac), purified IgG2a to rat LFA-1 alpha chain (CD11a).25 Negative controls consisted of substitution of the primary antibody with equivalent concentrations of both irrelevant murine IgG and phosphate-buffered saline.
Immunohistochemistry
Renal tissues were snap-frozen in isopentane, precooled in liquid nitrogen, and stored until use at -70°C. Cryostat sections (5 µm thick) were adhered on chromalaun/gelatin–coated microscope slides, air-dried, and processed by an alkaline phosphatase/anti–alkaline phosphatase (APAAP) method.
The cryostat sections were briefly fixed in cold acetone, air-dried, immersed in Tris-buffered saline (TBS, pH 7.4), and preincubated with 100% fetal calf serum for 30 minutes. Monoclonal anti–ICAM-1 or anti–LFA-1 diluted in 1% bovine serum albumin/TBS was applied for 60 minutes. After washing with TBS (three times for 5 minutes), the sections were incubated for 60 minutes with affinity-isolated and rat-absorbed rabbit to mouse immunoglobulins (1:25, Dako), and immunoreactivity was visualized by the APAAP complex as proposed by the manufacturer with the neufuchsin substrate kit (Dako) for detection. All incubations were carried out at room temperature in a humid chamber. The endogenous alkaline phosphatase was blocked with the use of levamisole (Sigma Chemical Co) at an end concentration of 10 mmol/L. The sections were light counterstained in hematoxylin for 10 seconds (Gill No. 3, Sigma), blued in running tap water (10 minutes), and mounted with Aquatex (Merck).
Evaluation of ICAM-1 Expression
A semiquantitative score was designed for assessment of the intensity and distribution of staining. ICAM-1 expression was scored on renal tubules as follows: 0=absent; 1=occasional, weak; 2=focal, mild to moderate; and 3=diffuse, moderate to marked staining of mainly proximal tubules. In the interstitial area, ICAM-1 expression was scored as follows: 0=normal, general slight staining; 1=local, mildly increased; 2=focal, moderately increased; and 3=diffuse, markedly increased. Sections with ICAM-1 staining that could not be clearly scored as above were grouped in an intermediate score. The sections were independently graded by three observers in a blinded manner.
Measurement of LFA-1–Positive Cells on Tissue Sections
Tubulointerstitial infiltration was measured by random selection of cortical areas and counting of the number of LFA-1–positive cells in 20 high-power fields (x250) per section by means of a 1-cm2 grid fitted into the eyepiece of the microscope; large blood vessels and glomeruli were avoided. Mean values were expressed as cells per millimeter squared ±SE. The number of perivascular LFA-1–positive cells was determined by examination of 30 vessels in each kidney section. Values are expressed as mean±SE positive cells per vessel. The number of LFA-1–positive cells per glomerular cross section was determined by evaluation of 60 glomeruli per section for each rat. Values are expressed as mean±SE positive cells per glomerulus.
Statistical Analysis
Data are expressed as mean±SE. Significance of differences between 2K1C and sham rats was assessed by the nonparametric Mann-Whitney U test. A value of P<.05 was considered significant. Significance of correlations was assessed by the nonparametric Spearman rank order correlation test. Statistics were carried out with CSS Statistica software (Statsoft).
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Results |
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Systolic BP was not increased during the first 4 days after clipping but was significantly elevated in 2K1C rats by day 7 (154±4 versus 117±6 mm Hg in sham, P<.05) and increased further thereafter (to 251±7 versus 126±7 mm Hg) (Fig 1
). Body weight of the 2K1C rats was lower, and the development of hypertension was associated with significant increases of the ratio of heart weight to body weight as well as kidney weight to body weight (Table). The relative weight of the left clipped kidney remained unchanged during the 28 days.
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In the kidneys of normotensive control rats (sham), ICAM-1 was expressed weakly in glomeruli and weakly to moderately in vascular endothelium (large vessels, peritubular capillaries) and interstitial cells as well as occasionally on tubular epithelial cells (Fig 2A and 2B). With the development of hypertension, a progressive increase of renal ICAM-1 expression was observed (Figs 2 and 3). Fig 3 shows the semiquantitative scores for the tubular and interstitial ICAM-1 of each kidney section during the progression of renal injury. In the prehypertensive phase (days 4 to 7), no significant changes in ICAM-1 staining could be seen in the renal cortex compared with control rats (Fig 3). At day 14, ICAM-1 expression was moderately increased focally (Figs 2C, 2D, and 3). A more diffuse, moderate to marked upregulation was seen in the tubulointerstitium and tubular epithelium at day 28 (Figs 2E, 2F, and 3). The tubular ICAM-1 staining pattern was most prominent on the luminal surface, particularly on the proximal tubular brush borders. However, a cytoplasmic staining pattern was also apparent, especially at day 14, when the luminal expression of ICAM-1 was not yet so evident. At day 28, the strong tubular ICAM-1 positivity was associated with both increased interstitial peritubular ICAM-1–positive cells and tubulointerstitial damage. In addition, an augmented perivascular ICAM-1 staining was detectable. Changes of vascular endothelial ICAM-1 staining were difficult to assess because of the constitutive expression of ICAM-1 at this site. The glomerular ICAM-1 expression was unchanged; only a few single glomeruli showed an upregulation.
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) and kidneys from sham-operated control rats (
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In association with the renal ICAM-1 upregulation, there was an increased infiltration of LFA-1 (CD11a)–positive cells (Fig 4). At day 4, no increase in the number of renal LFA-1–positive cells could be detected, corresponding to the unchanged ICAM-1 staining. A progressive and significant tubulointerstitial (Fig 4A), perivascular (Fig 4B), and periglomerular (Fig 4D) influx of LFA-1–positive cells was seen by day 7, which reached the maximum at day 14 and remained elevated up to day 28. The values for the interstitial LFA-1–positive cells (cells per millimeter squared) were 52±4 versus 31±6 (P<.05, n=5) at day 7, 127±11 versus 32±3 (P<.005, n=5) at day 14, and 125±17 versus 33±4 (P<.05, n=5) at day 28. In contrast, glomerular infiltration of LFA-1–positive cells was not evident (Fig 4C). Fig 5 shows representative photomicrographs of the LFA-1 immunostaining. Only single interstitial and glomerular LFA-1–positive cells were detectable in the control kidney sections (Fig 5A). After 2 weeks of hypertension, LFA-1–positive infiltrating mononuclear cells were markedly accumulated in the perivascular (Fig 5B) and intertubular (Fig 5C) regions of the renal cortex, which was associated with the enhanced ICAM-1 staining.
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In addition, there was a positive relation between the increased expression of ICAM-1 in tubules and interstitial cells and the infiltration of LFA-1–positive cells in the tubulointerstitium (Fig 6). Furthermore, the interstitial LFA-1–positive cell infiltration (r=.75, P<.001, n=18) correlated with systolic BP in 2K1C but not in sham control rats.
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Discussion |
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Our results provide immunohistochemical evidence that ICAM-1 expression increases progressively in kidneys exposed to high BP in the 2K1C Goldblatt model. ICAM-1 induction was most marked in the renal tubular epithelium and cortical interstitial area, with little staining in glomeruli. Infiltration of mononuclear cells staining positive for LFA-1, the binding partner of ICAM-1, paralleled the upregulation of ICAM-1. Infiltration of LFA-1–positive leukocytes and ICAM-1 expression were related to the extent of the BP increase in the 2K1C model. Thus, our data suggest that the ICAM-1/LFA-1 pathway may be involved in mediating hypertensive renal injury.
The involvement of the ICAM-1/LFA-1 interaction in the recruitment of mononuclear cells has been examined in a number of inflammatory renal disorders, including different forms of glomerulonephritis 12 13 (reviewed in References 26 and 27), renal allograft rejection,14 28 29 and tubulointerstitial nephritis.15 Recent investigations have revealed that the in vivo administration of monoclonal anti–ICAM-1 and anti–LFA-1 prevented the renal injury in these inflammatory diseases.15 16 17 30
In addition, an upregulation of ICAM-1 has also been shown in atherosclerotic plaques in human blood vessels.31 32 33 Recently, Kelly et al18 reported ICAM-1 upregulation in ischemic acute renal failure in rats and observed a protective effect of monoclonal antibodies against ICAM-1 and LFA-1. Our data suggest that leukocyte infiltration via the ICAM-1/LFA-1 interaction is involved in hypertensive nephrosclerosis, another model of supposedly noninflammatory renal disease.
Hypertensive nephrosclerosis is an important cause of end-stage renal failure.34 In addition, hypertensive renal injury contributes to the maintenance of high BP.35 Recently, we observed that the most striking changes occurred in the tubulointerstitium, including matrix expansion, cell proliferation, and mononuclear cell infiltration, whereas glomerular changes were rather subtle in comparison.1 Eng et al2 and Veniant et al,36 who recently studied the same model of 2K1C nephrosclerosis, confirmed our findings. Different types of inflammatory injury have been described in other models of hypertensive nephrosclerosis. Raji et al37 described complement-mediated glomerular damage in deoxycorticosterone acetate–salt hypertensive mice.
The progression of hypertensive injury in the 2K1C model was accompanied by a marked induction of ICAM-1 in tubular and interstitial cells as well as an interstitial influx of LFA-1–positive cells. However, the glomerular ICAM-1 level was unchanged. A similar pattern of ICAM-1 expression has been reported in biopsies of renal allograft rejection14 28 29 and in a murine model of hereditary tubulointerstitial nephritis.15 In contrast, increased glomerular expression of ICAM-1 has been described in several primary glomerular diseases.26 27 38
The role of endothelial ICAM-1 in adhesion and transendothelial migration of mononuclear cells is well established.9 10 39 40 41 However, the role of increased tubular ICAM-1 expression in tubulointerstitial injury is not clear. We cannot exclude reabsorption of filtered, soluble ICAM-1 or immunoreactive fragments at this stage. However, in the earlier phase (days 4 through 14), the localization of tubular ICAM-1 staining appeared to be more cytoplasmic, and apical ICAM-1 expression was not yet so evident. During this period, the infiltration of LFA-1–positive cells reached its maximum and the level remained elevated.
Other researchers have argued that tubular ICAM-1 contributes to mononuclear cell recruitment.13 42 43 44 45 Markovic-Lipkovski et al42 and Muller et al43 reported abnormal ICAM-1 expression on the proximal tubular brush border in association with aberrant tubular basolateral major histocompatibility complex class II antigen expression, and it has been postulated that the tubular epithelial cell may act as an antigen-presenting cell promoting tubular damage. A recent report from Pichler et al46 supports the concept that tubular cells contribute to mononuclear cell infiltration and fibrosis in a model of interstitial fibrosis. In rats treated with cyclosporine, tubular expression of the macrophage adhesive protein osteopontin correlated with mononuclear cell infiltration and peritubular fibrosis.46 A recent ultrastructural study demonstrated that the upregulation of periglomerular/peritubular capillary ICAM-1 promotes the entry of mononuclear cells into the interstitium and that the observed close interaction of these cells with potentially antigen-presenting interstitial fibroblast-like cells may facilitate their movement and localization within the interstitium.11 Whatever the precise mechanisms may be, the positive relation between the tubular and interstitial ICAM-1 score and the accumulation of interstitial LFA-1–positive cells in our model suggests an involvement of tubular and/or interstitial cells in attracting the mononuclear cells.
We can only speculate on the molecular and cellular mechanisms leading to ICAM-1 expression in our model. In endothelial cells, shear stress has been shown to induce the expression of ICAM-1 but not of other adhesion molecules.47 Our data are in agreement with this notion because ICAM-1 expression became evident only with the development of high BP, which conceivably produces increased shear stress for the vascular endothelium. The stimulation of the renin-angiotensin system in the 2K1C model might also contribute to changes in the composition of the vascular wall, although we are not aware of reports describing an effect of angiotensin II on ICAM-1 expression. However, the peptide may activate mononuclear cells48 and thus facilitate recruitment of these cells to renal tissue. Furthermore, angiotensin II may act synergistically with some cytokines capable of inducing ICAM-1 expression.49 In addition, localized ischemia could contribute to ICAM-1 expression18 in later stages of 2K1C hypertension, when blood vessel occlusion occurs,1 2 but is probably not present for the first 2 weeks after clipping.
Whatever the initial trigger for ICAM-1 expression might be, infiltrating LFA-1–positive mononuclear cells may induce structural damage once the process is started. Cytotoxic mediators released by these cells could damage tubular cells and contribute to the disruption of tubular architecture often seen in this model. Cytokines released by mononuclear cells could induce the expression of extracellular matrix expansion in the nonclipped kidney.1 In addition, these cytokines could further enhance local ICAM-1 expression, thus leading to infiltration of more mononuclear cells. Thus, our results emphasize the notion that inflammatory mechanisms contribute to hypertensive renal injury. We speculate that interventions to block the infiltration of mononuclear cells might alleviate the structural renal damage caused by high BP. Future experiments attempting the blockade of the ICAM-1/LFA-1 interaction will be necessary to define the precise role of mononuclear cell infiltration in hypertensive nephrosclerosis relative to tubular cell proliferation or the possible direct effects of angiotensin II on matrix expansion.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by a grant-in-aid to H.G. (Ge 568/2-2) from the Deutsche Forschungsgemeinschaft (DFG), Bonn-Bad Godesberg, Germany. K.F.H. is the recipient of a DFG research scholarship (Hi 510/5-1).
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Footnotes |
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Presented in part at The American Society of Nephrology 26th Annual Meeting, Boston, Mass, November 14-17, 1993.
Received January 22, 1996; first decision February 22, 1996; accepted July 10, 1996.
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D. N. Muller, E. M. A. Mervaala, F. Schmidt, J.-K. Park, R. Dechend, E. Genersch, V. Breu, B.-M. Loffler, D. Ganten, W. Schneider, et al. Effect of Bosentan on NF-{kappa}B, Inflammation, and Tissue Factor in Angiotensin II-Induced End-Organ Damage Hypertension, August 1, 2000; 36(2): 282 - 290. [Abstract] [Full Text] [PDF]
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F. C. Luft, E. Mervaala, D. N. Muller, V. Gross, F. Schmidt, J. K. Park, C. Schmitz, A. Lippoldt, V. Breu, R. Dechend, et al. Hypertension-Induced End-Organ Damage : A New Transgenic Approach to an Old Problem Hypertension, January 1, 1999; 33(1): 212 - 218. [Abstract] [Full Text] [PDF]
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E. M. A. Mervaala, D. N. Muller, J.-K. Park, F. Schmidt, M. Lohn, V. Breu, D. Dragun, D. Ganten, H. Haller, and F. C. Luft Monocyte Infiltration and Adhesion Molecules in a Rat Model of High Human Renin Hypertension Hypertension, January 1, 1999; 33(1): 389 - 395. [Abstract] [Full Text] [PDF]
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