CD59a Deficiency Exacerbates Ischemia-Reperfusion Injury in Mice

Turnberg, Daniel; Botto, Marina; Lewis, Margarita; Zhou, Wuding; Sacks, Steven H.; Morgan, B. Paul; Walport, Mark J.; Cook, H. Terence

doi:10.1016/s0002-9440(10)63345-7

Cited by 37 publications

(29 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, C5b appears to prime C6 by inducing conformational changes toward the open conformation. cient in CD59 suffered more tubular injury than wild type littermates (61).…”

Section: Discussionmentioning

confidence: 89%

Crystal Structure of C5b-6 Suggests Structural Basis for Priming Assembly of the Membrane Attack Complex

Aleshin

DiScipio

Stec

et al. 2012

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: The C5b-6 complex triggers assembly of the Membrane Attack Complex. Results: The structure of C5b-6 at 4.2 Å resolution allowed an atomic model to be built. Conclusion: C5b is stabilized by an interdomain linker of C6 and N-terminal elements that simultaneously engage N-and C-terminal elements. Significance: In stabilizing C5b, C6 must change its conformation so that it becomes "primed" for initiating MAC assembly.

show abstract

“…Thus, C5b appears to prime C6 by inducing conformational changes toward the open conformation. cient in CD59 suffered more tubular injury than wild type littermates (61).…”

Section: Discussionmentioning

confidence: 89%

Crystal Structure of C5b-6 Suggests Structural Basis for Priming Assembly of the Membrane Attack Complex

Aleshin

DiScipio

Stec

et al. 2012

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…The experiment was repeated using IgG and Fab fragments of the 5D5 antibody, and LDH release was similar in the 2 groups. deficient in DAF and CD59 are susceptible to complement-mediated injury after renal I/R (19,20), likely due to complement activation along the vascular endothelium (19). However, extensive complement activation after I/R in wild-type mice occurs along the tubular epithelium.…”

Section: Figurementioning

confidence: 99%

“…DAF and CD59 expression is limited to the glomeruli and renal arteries (17,18). Deficiency in DAF alone or DAF and CD59 results in vascular complement activation after I/R and worse renal injury (19,20). However, substantial vascular complement activation does not occur in wild-type mice after I/R (2).…”

Section: Introductionmentioning

confidence: 99%

Altered renal tubular expression of the complement inhibitor Crry permits complement activation after ischemia/reperfusion

Thurman¹

2006

Journal of Clinical Investigation

154

168

View full text Add to dashboard Cite

Ischemia/reperfusion (I/R) of several organs results in complement activation, but the kidney is unique in that activation after I/R occurs only via the alternative pathway. We hypothesized that selective activation of this pathway after renal I/R could occur either because of a loss of complement inhibition or from increased local synthesis of complement factors. We examined the relationship between renal complement activation after I/R and the levels and localization of intrinsic membrane complement inhibitors. We found that loss of polarity of complement receptor 1-related protein y (Crry) in the tubular epithelium preceded activation of the alternative pathway along the basolateral aspect of the tubular cells. Heterozygous gene-targeted mice that expressed lower amounts of Crry were more sensitive to ischemic injury. Furthermore, inhibition of Crry expressed by proximal tubular epithelial cells in vitro resulted in alternative pathway-mediated injury to the cells. Thus, altered expression of a complement inhibitor within the tubular epithelium appears to be a critical factor permitting activation of the alternative pathway of complement after I/R. Increased C3 mRNA and decreased factor H mRNA were also detected in the outer medulla after I/R, suggesting that altered synthesis of these factors might further contribute to complement activation in this location.

show abstract

“…In contrast to humans, mice have two isoforms of CD59: CD59a, which is widely expressed, and CD59b, which is predominantly limited to the testes (6). We have shown previously that mice lacking CD59a are more susceptible to glomerular immune complex injury (7) and to tubular injury and interstitial inflammation following ischemia-reperfusion injury (8).…”

mentioning

confidence: 99%

Complement Activation Contributes to Both Glomerular and Tubulointerstitial Damage in Adriamycin Nephropathy in Mice

Turnberg

Lewis

Moss

et al. 2006

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Adriamycin nephropathy is a model of focal segmental glomerulosclerosis, characterized by proteinuria and progressive glomerulosclerosis and tubulointerstitial damage. In this study, we examined the role of complement in the etiology of adriamycin nephropathy in mice. We used mice deficient in C1q, factor D, C3, and CD59, and compared them with strain-matched controls. C3 deposition occurred in the glomeruli of wild-type mice as early as 48 h following a single i.v. injection of adriamycin. C3-deficient mice developed significantly less proteinuria and less podocyte injury at day 3 postadriamycin than controls, suggesting that complement is important in mediating the early podocyte injury. At later time points, C3-deficient mice were protected from glomerulosclerosis, tubulointerstitial injury, and renal dysfunction. Factor D-deficient mice were also protected from renal disease, confirming the importance of alternative pathway activation in this model. In contrast, C1q-deficient mice developed similar disease to controls, indicating that the complement cascade was not activated via the classical pathway. CD59-deficient mice, which lack adequate control of C5b-9 formation, developed significantly worse histological and functional markers of renal disease than controls. Interestingly, although more C9 deposited in glomeruli of CD59-deficient mice than controls, in neither group was tubulointerstitial C9 staining apparent. We have demonstrated for the first time that alternative pathway activation of complement plays an important role in mediating the initial glomerular damage in this in vivo model of focal segmental glomerulosclerosis. Lack of CD59, which regulates the membrane attack complex, led to greater glomerular and tubulointerstitial injury.

show abstract

CD59a Deficiency Exacerbates Ischemia-Reperfusion Injury in Mice

Cited by 37 publications

References 42 publications

Crystal Structure of C5b-6 Suggests Structural Basis for Priming Assembly of the Membrane Attack Complex

Crystal Structure of C5b-6 Suggests Structural Basis for Priming Assembly of the Membrane Attack Complex

Altered renal tubular expression of the complement inhibitor Crry permits complement activation after ischemia/reperfusion

Complement Activation Contributes to Both Glomerular and Tubulointerstitial Damage in Adriamycin Nephropathy in Mice

Contact Info

Product

Resources

About