Enhancing complement control on endothelial barrier reduces renal post-ischemia dysfunction - PubMed (original) (raw)

Enhancing complement control on endothelial barrier reduces renal post-ischemia dysfunction

Sathnur B Pushpakumar et al. J Surg Res. 2011 Oct.

Abstract

Background: Excessive complement activation is an integral part of ischemia and reperfusion (IR) injury (IRI) of organs. In kidney transplantation, the pathologic consequence of IRI and complement activation can lead to delayed graft function, which in turn is associated with acute rejection. Previous strategies to reduce complement-induced IRI required systemic administration of agents, which can lead to increased susceptibility to infections/immune diseases. The objective of this study was to determine whether an increase in complement control defenses of rat kidney endothelium reduces IRI. We hypothesized that increased complement control on the endothelial barrier reduces IR-mediated complement activation and reduces kidney dysfunction.

Materials and methods: Fischer 344 rats underwent left kidney ischemia for 45 min and treatment with a novel fusogenic lipid vesicle (FLVs) delivery system to decorate endothelial cells with vaccinia virus complement control protein (VCP), followed by reperfusion for 24 h. Assessment included renal function by serum creatinine and urea, myeloperoxidase assay for neutrophil infiltration, histopathology, and quantification of C3 production in kidneys.

Results: Animals in which the kidney endothelium was bolstered by FLVs+VCP treatment had better renal function with a significant reduction in serum creatinine compared with vehicle controls (P < 0.05). Also, C3 production was significantly reduced (P < 0.05) in treated animals compared with vehicle controls.

Conclusion: Increasing complement control at the endothelial barrier with FLVs+VCP modulates complement activation/production during the first 24 h, reducing renal dysfunction following IRI.

Copyright © 2011 Elsevier Inc. All rights reserved.

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Conflict of interest statement

The authors Sathnur Pushpakumar, Chirag Soni, Rong Wan, Nathan Todnem, Phani K Patibandla, Tathyana Fensterer, Qunwei Zhang, John H. Barker, do not have any conflict of interest.

Figures

Figure 1

Figure 1

Animals treated with FLVs+VCP (Fusogenic lipid vesicles and Vaccinia virus complement control protein) maintain better renal function. Creatinine was analyzed from blood samples collected before inducing IRI and after 24h of reperfusion. Control animals which received lactated Ringer’s solution only, show 7 fold increase in serum creatinine as compared to <3 fold in the FLVs+VCP group (*P<0.05). Values are represented as means±SEM (n=6/group).

Figure 2

Figure 2

There was no difference in the serum urea levels between the groups. Serum urea was measured similar to creatinine as described in Figure 1. Values are represented as means±SEM (n=6/group).

Figure 3

Figure 3

Kidney samples were collected as described in the materials and methods section. Kidney injury was scored according to Jablonski’s criteria Grades 1–4. Representative histology pictures at 20x from: a) sham rats, b) control kidney (lactated Ringer’s solution perfusion) shows extensive damage of the tubules and glomeruli including necrosis (arrows), c) FLVs+VCP treated kidney shows preservation of normal architecture with moderate tubular damage (arrow) and lesser neutrophil infiltration, d) VCP treated animal shows minimal damage and decreased neutrophil infiltration, and e) FLVs treated kidney shows moderate injury and neutrophil infiltration.

Figure 4

Figure 4

Effect of treatments on MPO activity as a marker for neutrophil infiltration into the tissues. VCP therapy by itself shows significantly reduced MPO activity (P<0.05) and treatment with FLVs+VCP and FLVs shows a downward trend. Control group shows increased levels indicating marked neutrophil influx. Values are represented as means±SEM (n=6/group).

Figure 5

Figure 5

A. Graph of Western blot analysis comparing the deposition of C3 in kidneys from all groups (n=3/group). Excessive C3 deposits in the kidney homogenates was significantly decreased in the FLVs+VCP treated group as compared to control (P<0.05). B. Representative blot from a complete set of experiments.

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