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Title: Role of leukocytes, complement system and endothelium in rat renal ischaemia-reperfusion injury
Author: Nesargikar, Prabhu
ISNI:       0000 0004 5371 0305
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2015
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Introduction: Renal Ischaemia-Reperfusion injury (IRI) is a complex mechanism involving the interplay between endothelium, leukocytes and the complement system. To evaluate the role of these three key mediators, a rat model was used to evaluate changes seen in renal IRI. Two interventional agents: Anti-Thymocyte Globulin (ATG) and Soluble Complement Receptor-1 (sCR1) were used to modulate leukocyte and complement response in this IRI model with a view to assess, and define IRI mechanism. Methods: The Ischaemia-Reperfusion (IR) model involved unilateral left renal ischemia (n=10) for 40 minutes, followed by 48 hours of reperfusion. ATG (n=8), ATG Isotype (n=8) and sCR1(n=8) were given IV prior to the laparotomy followed by IR model. The sham group (n=6) served as controls. Blood CD3 lymphocyte counts and CH50 complement assay were used to check efficacy of ATG and sCR1 respectively. The kidneys retrieved at 48 hours were analysed for histology, immunohistochemistry and RT-qPCR studies. Results: The IR group showed significant injury compared to the sham group. ATG treatment offered significant histological protection mainly via decreased leukocyte infiltrate and endothelial protection compared to the IR and Isotype controls. CH50 assay showed complete ablation of complement activity at the time of reperfusion, with return to normality at 24 hours. sCR1 treatment conferred protection from IRI predominantly via suppression of the complement cascade (C3, C9), reduced leukocyte infiltrates and V endothelial protection. RT-qPCR showed down-regulation of injury molecules – KIM-1 and NGAL in both the intervention groups. Conclusion: Modulation of leukocytes and complement system using single dose ATG and sCR1 led to significant endothelial protection, resulting in amelioration of renal ischaemia-reperfusion injury. The complement system was ablated at the time of reperfusion and was reconstituted by 24 hours, thus indicating that suppression of complement system during the phase of IR provides an avenue for mitigating IRI.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: R Medicine (General)