Abstract
The complement system, and specifically C5a, is involved in renal ischemia-reperfusion (IR) injury. The 2 receptors for complement anaphylatoxin C5a (C5aR1 and C5aR2) are expressed on leukocytes as well as on renal epithelium. Extensive evidence shows that C5aR1 inhibition protects kidneys from IR injury; however, the role of C5aR2 in IR injury is less clear as initial studies proposed the hypothesis that C5aR2 functions as a decoy receptor. By Using wild-type, C5aR1(-/-), and C5aR2(-/-) mice in a model of renal IR injury, we found that a deficiency of either of these receptors protected mice from renal IR injury. Surprisingly, C5aR2(-/-) mice were most protected and had lower creatinine levels and reduced acute tubular necrosis. Next, an in vivo migration study demonstrated that leukocyte chemotaxis was unaffected in C5aR2(-/-) mice, whereas neutrophil activation was reduced by C5aR2 deficiency. To further investigate the contribution of renal cell-expressed C5aR2 vs. leukocyte-expressed C5aR2 to renal IR injury, bone marrow chimeras were created. Our data show that both renal cell-expressed C5aR2 and leukocyte-expressed C5aR2 mediate IR-induced renal dysfunction. These studies reveal the importance of C5aR2 in renal IR injury. They further show that C5aR2 is a functional receptor, rather than a decoy receptor, and may provide a new target for intervention.
Original language | English |
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Pages (from-to) | 3193-3204 |
Number of pages | 12 |
Journal | The FASEB Journal |
Volume | 31 |
Issue number | 7 |
Early online date | 10-Apr-2017 |
DOIs | |
Publication status | Published - Jul-2017 |
Keywords
- innate immunity
- PMNs
- kidney
- ACUTE KIDNEY INJURY
- DONOR BRAIN-DEATH
- ISCHEMIA/REPERFUSION INJURY
- CHEMOATTRACTANT RECEPTOR
- 2 PARTS
- C5L2
- ACTIVATION
- CELLS
- ANAPHYLATOXIN
- PATHWAY