期刊
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
卷 23, 期 9, 页码 1474-1485出版社
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2011111072
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资金
- Medical Research Council of the United Kingdom
- Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre award
- St Thomas's NHS Foundation Trust
- King's College London and King's College Hospital NHS Foundation Trust
- Medical Research Council [MR/J006742/1, G1001141, G0601202, G0600892, G0600698B] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0510-10142] Funding Source: researchfish
- MRC [G0601202, G0600892] Funding Source: UKRI
Renal ischemia reperfusion injury triggers complement activation, but whether and how the small proinflammatory fragments C3a and C5a contribute to the pathogenesis of this injury remains to be elucidated. Using C3aR-, C5aR-, or C3aR/C5aR-deficient mice and models of renal ischemia-reperfusion injury, we found that deficiency of either or both of these receptors protected mice from injury, but the C3aR/C5aR- and C5aR-deficient mice were most protected. Protection from injury was associated with less cellular infiltration and lower mRNA levels of kidney injury molecule-1, proinflammatory mediators, and adhesion molecules in postischemic kidneys. Furthermore, chimera studies showed that the absence of C3aR and C5aR on renal tubular epithelial cells or circulating leukocytes attenuated renal ischemia-reperfusion injury. In vitro, C3a and C5a stimulation induced inflammatory mediators from both renal tubular epithelial cells and macrophages after hypoxia/reoxygenation. In conclusion, although both C3a and C5a contribute to renal ischemia-reperfusion injury, the pathogenic role of C5a in this injury predominates. These data also suggest that expression of C3aR and C5aR on both renal and circulating leukocytes contributes to the pathogenesis of renal ischemia-reperfusion injury.
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