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Effects of Alterations of Glomerular Fibrin Deposition on Renal Inflammation in Rats at Different Age Stages

Department of Nephrology, Kidney Center and Key Lab of PLA, General Hospital of PLA, Beijing, People's Republic of China.

Address correspondence to Xiangmei Chen, MD, PhD, Department of Nephrology, Kidney Center and Key Lab of PLA, General Hospital of PLA, Fuxing Road 28, Beijing 100853, P.R. China. E-mail: xmchen{at}public.bta.net.cn

	Abstract

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Recent data indicated that aging accelerated glomerular fibrin deposition induced by lipopolysaccharide (LPS) in mice. Our hypothesis was that aging may exacerbate glomerular inflammatory responses induced by glomerular fibrin deposition. Both young and aged rats with glomerular fibrin deposition induced by LPS were treated with tranexamic acid (TA) and TA plus urokinase (UK). Infiltrating inflammatory cells and expressions of monocyte chemoattractant protein 1, intercellular adhesion molecule 1, and vascular endothelial-cadherin were markedly upregulated in the LPS+TA group compared with the LPS group. Reduction of fibrin deposition in the LPS+TA+UK group was associated with downregulation of the above indices (p <.05), whereas the alteration of vascular endothelial-cadherin protein expression was negatively correlated with the fibrin deposition. There were also significant differences in increased expressions of monocyte chemoattractant protein 1 and intercellular adhesion molecule 1 between young and aged rats. These in vivo data demonstrated that fibrin deposition contributed to glomerular inflammatory responses, which could be exacerbated by aging.

Inflammation is the response of vascular tissue to damage. A central feature of inflammatory disease is the migration of leukocytes from the circulation across endothelium and into the affected tissue (6). It has been demonstrated that leukocyte extravasation is a complex set of leukocyte–endothelial cell interactions, which involves rolling, adhesion, and transendothelial migration (diapedesis). Monocyte chemoattractant protein 1 (MCP-1) expressed on vascular endothelial cells can initiate recruitment and activation of leukocytes, whereas intercellular adhesion molecule 1 (ICAM-1) mediates leukocyte–endothelium adhesion. Vascular endothelial-cadherin (VE-Cad) acts as gatekeeper for the passage of leukocytes. These three molecules all play pivotal roles in control of leukocyte extravasation (6,7). Meanwhile, fibrin deposits on the surface of vascular endothelium; this depositing results from an imbalance between fibrin formation and fibrin removal (8,9). In vitro, fibrin is a potent vascular endothelial cell activator that directly contributes to leukocyte recruitment and activation by inducing MCP-1 and upregulation of ICAM-1 expression of vascular endothelial cells (10,11). Fibrin can also induce morphological changes of endothelial cells (12), and endothelial cell VE-Cad functions as a receptor for fibrin, which mediates their specific interactions (13).

Recent data suggested that fibrin(ogen) contributed to the pathogenesis of crescentic glomerulonephritis by promoting glomerular macrophage accumulation (14). However, until recently, few detailed studies have evaluated the proinflammatory effects of fibrin deposition contributing to leukocyte activation and recruitment via vascular endothelium in vivo. LPS can induce an activation of extrinsic coagulation cascade and trigger an imbalance between fibrin formation and removal resulting in fibrin deposition (15), and some studies revealed that experimental animals given LPS developed fibrin deposition in glomeruli (4,16).

In the present study, we hypothesized that aging may exacerbate glomerular inflammatory responses induced by glomerular fibrin deposition. Glomerular fibrin deposition was established by LPS administration in rats, and interfered with tranexamic acid (TA) and/or urokinase (UK), in order to investigate the proinflammatory effects of fibrin deposition on renal tissue and the disparity between different age stages, including the changes of mRNA and protein expression of MCP-1, ICAM-1, and VE-Cad.

	METHODS

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Reagents
LPS was purchased from Sigma Chemical Co. (St. Louis, MO) and dissolved in 0.9% saline before use. TA and UK were purchased from Dongting Pharmaceuticals Co., Ltd. (Hunan Province, China) and Fengyuan Pharmaceutical Factory (Anhui Province, China), respectively.

The following monoclonal and polyclonal antibodies were used in this study: mouse anti-rat monocytes/macrophages monoclonal antibody (ED1, Ectodysplasin A; Chemicon International, Inc., Temecula, CA), which labels monocytes and macrophages; mouse anti-rat CD11b (Mac-1 chain, WT.5; BD Pharmingen, San Diego, CA), which labels neutrophils and some myeloid cells; fluorescein isothiocyanate-conjugated fibrin polyclonal antibody (Dako Ltd., Glostrup, Denmark); mouse anti-rat ICAM-1 monoclonal antibody, goat anti-rat MCP-1, and VE-Cad polyclonal antibody were purchased from Santa Cruz Biotechnology Inc. (Santa Cruz, CA). Peroxidase-conjugated anti-mouse/goat IgG was purchased from Beijing Zhongshan Golden Bridge Biotechnology Co. Ltd. (Beijing, China).

Animals and Experimental Protocols
Young (3-month-old) and aged (27-month-old) female Wistar rats, weighing 220–260 g and 390–460 g, respectively, were obtained from Beijing Experimental Animal Center and cared for in accordance with the Guidelines for Animal Experiments. The animals were fed normal pellet food ad libitum and given water freely. Both young and aged rats were randomly divided into four groups, based on randomized block design, as follows: normal control group (NC group, n = 8), treated with saline alone (vehicle for LPS); LPS group, treated with LPS (14 mg/kg, intraperitoneal injection); LPS and TA group (LT group, n = 8), treated with TA (75 mg/kg, intraperitoneal injection 30 minutes after LPS administration); and LPS+TA+UK group (LTU group), treated with TA (75 mg/kg, intraperitoneal injection 30 minutes after LPS administration) and UK (25,000 U/kg, intravenous injection 60 minutes after LPS administration). Four hours after LPS injection, the rats were killed by overdose inhalation anesthesia with ether. Kidney tissues were rapidly harvested by standard dissection techniques, immediately frozen in liquid nitrogen for isolation of total RNA extracts, embedded immediately in Optimal Cutting Temperature compound (Miles Scientific, Naperville, IL) and snap-frozen in liquid nitrogen for immunofluorescence staining, or fixed in 10% neutral-buffered formalin overnight and embedded in paraffin for immunohistochemical staining as described below.

Immunofluorescence Staining for Fibrin, CD11b
Tissue sections frozen in Optimal Cutting Temperature compound (Miles Scientific), were cut into serial sections (4 µm thickness) on a cryostat and fixed in acetone for 5 minutes at room temperature. The detection of fibrin was performed by a direct method, using a fluorescein isothiocyanate-conjugated rabbit anti-fibrin antibody. Fluorescent images were obtained with a confocal laser scanning microscope (Bio-Rad MRC1024ES; Bio-Rad Laboratories Inc., Hercules, CA). Fibrin deposition in a minimum of 30 glomeruli per rat was evaluated quantitatively by measuring the intensity of the fluorescence in glomerular areas with LaserPix 4.0 software (Bio-Rad Laboratories). For the evaluation of infiltrating neutrophils, CD11b immunofluorescence staining was performed by indirect method. A minimum of 20 glomeruli was assessed per animal, and results were expressed as cells per glomerular cross section (c/gcs).

Immunohistochemical Staining for ED-1, MCP-1, ICAM-1, and VE-Cad
ED-1, MCP-1, ICAM-1, and VE-Cad were detected on 2-µm-thick sections by an indirect method using a mouse anti-rat monocytes/macrophages and ICAM-1, a goat anti-MCP-1, respectively, as follows. Briefly, the deparaffinized sections were incubated with each primary antibody overnight at 4°C, followed by biotinylated IgG of secondary antibody (Zhongshan SP kit). The sections were then reacted with horseradish peroxidase-conjugated streptavidin (Zhongshan SP kit). Color was then developed by incubation with an ImmunoPure Metal Enhanced Diaminobenzidine Substrate kit (Pierce, Rockford, IL).

Macrophages were detected with mouse anti-rat ED-1. Macrophages were quantified by counting the number of ED-1-positive cells per glomerulus. At least 20 random equatorial glomeruli cross sections per animal were counted. The percentages of MCP-1-, ICAM-1-, and VE-Cad-positive staining were quantitatively evaluated by measuring the positive areas and glomerular areas in 20 selected glomerular sections using TIPAS/88 Image software (Computer Center of Chinese PLA, China).

Northern Blot for MCP-1, ICAM-1, and VE-Cad
Total kidney RNA was extracted using a TRIzol kit (GIBCO BRL, Grand Island, NY) according to the manufacturer's directions. RNA (20 µg) was denatured and subjected to electrophoresis through a 1% agarose gel containing formaldehyde and transferred to Hybond N⁺ nylon membranes (Amersham Biosciences, Piscataway, NJ) by capillary action. The transferred RNAs were cross-linked to the nylon membrane by an ultraviolet light cross-linker. The quality of RNA was assessed by ethidium bromide staining. After transfer, the blots were prehybridized at 42°C for 3 hours. Then membranes were hybridized with each complementary DNA probe labeled by the random primer method (Boehringer Mannheim Biochemica, Mannheim, Germany) with [-³²P]-dCTP (deoxycytidine 5'-triphosphate) at 42°C for 20 hours. After hybridization, the blots were washed twice with 2 x standard saline citrate, 0.1% sodium dodecyl sulfate, and then once with 0.1 x standard saline citrate/0.1% sodium dodecyl sulfate at 42°C for 15 minutes. The hybridized membranes were exposed at –70°C for 72 hours. Autoradiography films (Kodak, Rochester, NY) were scanned using the UVP-2000 system. For quantitative densitometric measurements of northern blots, all the signals were normalized in comparison with the signals of 28S RNA. The complementary DNA probes used were MCP-1, ICAM-1, and VE-Cad. Primer sequence was as in Table 1.

	RESULTS

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Induction and Regulation of Glomerular Fibrin Deposition
Fibrin immunofluorescence staining was evaluated quantitatively by measuring the intensity of the fluorescence in glomerular areas (Figure 1). Fibrin deposition was hardly detected in glomeruli of young or aged rats in the NC group. In young or aged rats of all three treatment groups, the fibrin fluorescence intensity of the LT group was higher than that of the LPS group, whereas the fibrin fluorescence intensity of the LTU group was lower than that of the LT group (p <.05). The fibrin fluorescence intensity of the aged group was higher than that of the young group with the same treatment (p <.05). Meanwhile, the increased value of the fibrin fluorescence intensity in the aged group was greater than that in the young group (6.0 ± 0.4 vs 5.6 ± 0.3, p <.05).

View larger version (46K): [in this window] [in a new window]   Figure 1. Fibrin immunofluorescence staining. A, Representative confocal laser scanning photomicrograph. Original magnification x400. B, Fibrin immunofluorescence staining density for each group. Data are expressed as mean ± standard deviation. *p <.05, **p <.01, vs lipopolysaccharide (LPS) and tranexamic acid (TA) group (LT group) within the same age group; p <.05, p <.01, aged vs young group with the same treatment; p <.05, increased value of aged vs young group (n = 8 per group). NC = normal control group; LTU = LPS+TA+urokinase group

View larger version (90K): [in this window] [in a new window]   Figure 2. ED-1(Ectodysplasin A) staining for glomerular macrophages. A, Representative photomicrograph immunohistochemistry staining of ED-1. Original magnification x400. B, ED-1-positive macrophage count was expressed as mean ± standard deviation. *p <.05, vs lipopolysaccharide (LPS) and tranexamic acid (TA) group (LT group) within same age group; p <.05, p <.01, aged vs young group with the same treatment; p <.05, increased value of aged vs young group (n = 8 per group). NC = normal control group; LTU = LPS+TA+urokinase group

View larger version (59K): [in this window] [in a new window]   Figure 3. CD11b immunofluorescence staining. A, Representative confocal laser scanning photomicrograph. Original magnification x400. B, CD11b immunofluorescence staining positive cells. Data were expressed as mean ± standard deviation. *p <.05 vs lipopolysaccharide (LPS) and tranexamic acid (TA) group (LT group) within the same age group; p <.05, p <.01, aged vs young group with the same treatment; p <.05, increased value of aged vs young group (n = 8 per group). NC = normal control group; LTU = LPS+TA+urokinase group

View larger version (79K): [in this window] [in a new window]   Figure 4. Monocyte chemoattractant protein 1 (MCP-1 ) and messenger RNA expressions. A, Representative photomicrograph immunohistochemistry staining of MCP-1. Original magnification x400. B, Immunohistochemistry quantitative analysis for the percentage of MCP-1-positive stained glomerular area. C, Representative northern blot. D, Densitometric analysis of northern blots. Results were expressed as mean ± standard deviation. *p <.05, vs lipopolysaccharide (LPS) and tranexamic acid (TA) group (LT group) within the same age group; p <.05, p <.01, aged vs young group with the same treatment; p <.05, increased value of aged vs young group (n = 8 per group). NC = normal control group; LTU = LPS+TA+urokinase group

View larger version (18K): [in this window] [in a new window]   Figure 4. Continued

View larger version (93K): [in this window] [in a new window]   Figure 5. Intercellular adhesion molecule 1 (ICAM-1) protein and messenger RNA expressions. A, Representative photomicrograph immunohistochemistry staining of ICAM-1. Original magnification x400. B, Immunohistochemistry quantitative analysis for the percentage of ICAM-1-positive stained glomerular area. C, Representative northern blot. D, Densitometric analysis of northern blots. The results were expressed as mean ± standard deviation. *p <.05 vs lipopolysaccharide (LPS) and tranexamic acid (TA) group (LT group) within the same age group; p <.05, p <.01 vs young group with the same treatment; p <.05, increased value of aged vs young group (n = 8 per group). NC = normal control group; LTU = LPS+TA+urokinase group

View larger version (20K): [in this window] [in a new window]   Figure 5. Continued

View larger version (52K): [in this window] [in a new window]   Figure 6. Vascular endothelial–cadherin (VE-Cad) protein and messenger RNA expressions. A, Representative photomicrograph immunohistochemistry staining of VE-Cad. Original magnification x400. B, Immunohistochemistry quantitative analysis for the percentage of VE-Cad-positive stained glomerular area. C, Representative northern blot. D, Densitometric analysis of northern blots. The results were expressed as mean ± standard deviation. *p <.05 vs lipopolysaccharide (LPS) and tranexamic acid (TA) group (LT group) within the same age group; p <.05, p <.01 vs young group with the same treatment (n = 8 per group). NC = normal control group; LTU = LPS+TA+urokinase group

	DISCUSSION

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Our results demonstrated that there was no fibrin deposition in glomeruli of either young or aged normal rats, suggesting that fibrin formation and removal maintains a fine balance under physiological status. After LPS administration, the aged rats displayed glomerular fibrin deposition, whereas fibrin was hardly detected in the young rats. When treated with a combination of LPS and TA, fibrin deposition was significantly increased in both young and aged rats, and the intensity of fibrin deposition in aged rats was higher than that in young rats. Furthermore, fibrin deposition was markedly decreased in the young and aged LPS+TA+UK treatment groups. These results showed that TA and UK could interfere with the level of glomerular fibrin deposition by inhibiting or promoting fibrin removal, respectively. The animal model and methods used in this study facilitated investigating the effect of glomerular fibrin deposition on renal tissue. Previously, to explore the contribution of fibrin to glomerular diseases, both ancrod and fibrinogen-knocking out were used to deplete circulating fibrinogen (14,17). However, both ancrod and fibrinogen-knocking out were used mainly for reduction of fibrin deposition by intervening fibrin formation with depletion of fibrinogen. Interestingly, both young and aged rats received the same treatment, but there were significant differences between them in fibrin deposition, suggesting that there was a difference in response to the same stimuli between young and aged rats. Taken together, aged rats were more susceptible to development of fibrin deposition, indicating that aging accelerated glomerular fibrin deposition, which was consistent with the report of Yamamoto and colleagues (4).

The major effector cell is the macrophage, which is the nexus between the coagulation pathway and inflammation, and participates in regulation of the cell surface tissue factor during inflammation (18). Most of the infiltrating cells were neutrophils during the acute phase of this model induced by LPS (19). Therefore, we evaluated the extent of infiltration of both macrophages and neutrophils in the glomeruli. Immunohistochemical staining for macrophages and immunofluorescence staining for neutrophils revealed that the more glomerular infiltrating cells and fibrin deposition were found in both young and aged rats treated with a combination of LPS and TA than in rats treated with only LPS. In contrast, less glomerular infiltration and fibrin deposition were found in rats treated with a combination of LPS, TA, and UK than in rats treated with a combination of LPS and TA. These results indicated that fibrin deposition facilitated inflammatory cell infiltration, which was consistent with the results found in an experiment with fibrinogen-deficient mice (14). In our study, both TA and UK used for controlling the fibrin deposition were through intervening in fibrin removal. Interestingly, the number of infiltrating cells in the glomeruli of aged rats was also significantly higher than that of young rats with the same treatment. We further found that there was a significant difference in the increased number of infiltrating cells in response to fibrin deposition between young and aged rats. These data showed that aged rats were susceptible to proinflammatory effects of fibrin deposition, implying that aging may promote the proinflammatory effects induced by the glomerular fibrin deposition.

To further explore the proinflammatory effects of fibrin deposition, we determined the changes of MCP-1, ICAM-1, VE-Cad protein, and mRNA expressions. Consistent with two previous studies in vitro (11,12), we also found that fibrin deposition upregulated MCP-1, ICAM-1 protein, and mRNA expressions, whereas VE-Cad protein abundance was downregulated. However, the level of VE-Cad mRNA expression was upregulated by fibrin deposition. Downregulated VE-Cad protein might be interpreted by VE-Cad internalization and degradation after endothelial injury, VE-Cad protein will be upregulated when tissue repairs (20,21). MCP-1, ICAM-1, and VE-Cad are important molecules involved in leukocyte extravasation. In glomerulus, MCP-1 is mainly detected in vascular endothelial cells. MCP-1 expressed on the surface of endothelial cells interacts with their cognate receptors on specific leukocytes, which trigger the activation of adhesion molecules and result in firm adhesion (22). ICAM-1 mediates firm adhesion between leukocyte and endothelial cell. It has been reported that ICAM-1 can recognize bridging ligand fibrin (ogen) (23). VE-Cad is exclusively expressed on vascular endothelial cells, and is the major adhesive molecule at endothelial adherens junctions and plays a role in maintaining integrity and regulating permeability of vascular endothelial cells (24). Recent data revealed that VE-Cad acts as a gatekeeper for the passage of leukocytes (7), which derived from the blockade of VE-Cad increases the rate of neutrophil extravasation in vivo (25). Downregulation of VE-Cad in intimal neovessels was closely related to changes in intimal inflammation (26). Furthermore, fibrin interaction with VE-Cad can lead to endothelial cell and cytoskeletal reorganization (13). Upregulation of MCP-1 and ICAM-1 expression and downregulation of VE-Cad expression suggest that vascular endothelial activation and/or injury and proinflammatory vascular endothelium developed and correlated with control of leukocyte extravasation (27,28). Leukocyte extravasation from the blood into the tissues is a regulated multistep process involving a series of coordinated interactions between leukocytes and endothelial cells. It means leukocyte extravasation is dependent on the control of molecules mentioned above. A central feature of inflammatory diseases is the migration of leukocytes from the circulation across the endothelium and into the affected tissue. As a result, fibrin deposition upregulated MCP-1 and ICAM-1 expression, downregulated VE-Cad expression, and facilitated glomerular inflammatory cell infiltration. In addition, there was a significant difference in the increased expressions of MCP-1 and ICAM-1 between young and aged rats, suggesting that aging could exacerbate vascular endothelial injury and lead to proinflammatory endothelium development. However, no significant difference was found in the increased VE-Cad expression induced by fibrin deposition between young and aged rats, indicating that aging displayed a disparity in its effects on changes induced by fibrin deposition.

Summary
Our findings have provided substantial evidence that glomerular fibrin deposition contributes to inflammatory responses, which is characterized by inflammatory infiltration and endothelial injury in vivo, and that aging can promote glomerular fibrin deposition and subsequent inflammatory responses. These results have provided novel insights into the associations of glomerular fibrin deposition, inflammation, and aging.

	Acknowledgments

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This work was supported by the Major State Basic Research Development Program of China (G2000057000), the Creative Research Group Fund of the National Natural Science Foundation of China (30121005), and National Natural Science Foundation of China (30470803).

An abstract of this work was presented at the 2004 annual meeting of the American Society of Nephrology.

	Footnotes

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Decision Editor: James R. Smith, PhD

Received January 27, 2005

Accepted April 14, 2005

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