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A Murine Closed-chest Model of Myocardial Ischemia and Reperfusion
Published on: July 17, 2012
CD59a deficiency exacerbates ischemia-reperfusion injury in mice
Daniel Turnberg1, Marina Botto, Margarita Lewis
1Rheumatology Section, Eric Bywaters Centre, London, United Kingdom.
Insights
Mice lacking CD59a showed worsened kidney injury after ischemia-reperfusion. Uncontrolled membrane attack complex deposition exacerbated tubular damage and leukocyte infiltration, highlighting CD59a's protective role.
Area of Science:
- Nephrology
- Immunology
- Pathophysiology
Background:
- Terminal complement components, C5a and the membrane attack complex (MAC), contribute to ischemia-reperfusion injury (IRI).
- CD59 is a key regulator of MAC formation, preventing cell lysis.
Purpose of the Study:
- To investigate the role of CD59 in renal IRI using mice deficient in the Cd59a gene (mCd59a-/-).
Main Methods:
- Unilateral renal IRI was induced by clamping the renal pedicle for 30 minutes.
- Mice were analyzed at 72 hours and 2 weeks post-IRI.
- Histological injury, apoptosis, neutrophil influx, and C9 deposition were quantified.
Main Results:
- mCd59a-/- mice exhibited significantly increased tubular injury, tubulointerstitial apoptosis, and neutrophil influx at 72 hours post-IRI.
- At 2 weeks, mCd59a-/- mice showed more severe tubular damage and greater lymphocyte infiltration.
- Increased C9 deposition, a marker of MAC, was observed in mCd59a-/- mice at both time points.
Conclusions:
- The absence of CD59a leads to unregulated MAC deposition.
- This exacerbates both tubular injury and interstitial leukocyte infiltration following renal IRI.
- CD59a plays a critical protective role in mitigating renal IRI.
Abstract:
The terminal complement components C5a and the membrane attack complex are involved in the pathogenesis of ischemia-reperfusion injury in many organs. CD59 is the major regulator of membrane attack complex formation. Mice deficient in the Cd59a gene (mCd59a-/-) were used to investigate the role of CD59 in renal ischemia-reperfusion injury. Unilateral ischemia-reperfusion injury was induced by clamping the left renal pedicle for 30 minutes under general anesthetic. Mice were studied at 72 hours and 2 weeks after ischemia-reperfusion injury. mCd59a-/- mice developed significantly greater tubular injury (P = 0.01), tubulointerstitial apoptosis (P = 0.02), and neutrophil influx (P = 0.04) than controls at 72 hours after ischemia-reperfusion. Two weeks after ischemia-reperfusion, mCd59a-/- mice exhibited more severe tubular damage predominantly in a corticomedullary distribution than controls (P = 0.02). Quantification of interstitial leukocytes revealed significantly greater numbers of infiltrating lymphocytes (but not macrophages) in mCd59a-/- mice than controls (P = 0.04) at 2 weeks. At both time points, significantly more C9 (as a marker of membrane attack complex) deposition occurred in a peritubular distribution in mCd59a-/- mice than controls. In conclusion, these results demonstrate that the lack of CD59a, by allowing unregulated membrane attack complex deposition, exacerbates both the tubular injury and the interstitial leukocyte infiltrate after ischemia-reperfusion injury in mice.
