CCR2 signaling contributes to ischemia-reperfusion injury in kidney.
Examined were CCR2-deficient mice to clarify the contribution of macrophages via monocyte chemoattractant protein 1 (MCP-1 or CCL2)/CCR2 signaling to the pathogenesis of renal ischemia-reperfusion injury. Also evaluated was the therapeutic effects via the inhibition of MCP-1/CCR2 signaling with propagermanium (3-oxygermylpropionic acid polymer) and RS-504393. Renal artery and vein of the left kidney were occluded with a vascular clamp for 60 min. A large number of infiltrated cells and marked acute tubular necrosis in outer medulla after renal ischemia-reperfusion injury was observed. Ischemia-reperfusion induced the expression of MCP-1 mRNA and protein in injured kidneys, followed by CCR2-positive macrophages in interstitium in wild-type mice. The expression of MCP-1 was decreased in CCR2-deficient mice compared with wild-type mice. The number of interstitial infiltrated macrophages was markedly smaller in the CCR2-deficient mice after ischemia-reperfusion. CCR2-deficient mice decreased the number of interstitial inducible nitric oxide synthase-positive cells after ischemia-reperfusion. The area of tubular necrosis in CCR2-deficient mice was significantly lower than that of wild-type mice after ischemia-reperfusion. In addition, CCR2-deficient mice diminished KC, macrophage inflammatory protein 2, epithelial cell-derived neutrophil-activating peptide 78, and neutrophil-activating peptide 2 expression compared with wild-type mice accompanied with the reduction of interstitial granulocyte infiltration. Similarly, propagermanium and RS-504393 reduced the number of interstitial infiltrated cells and tubular necrosis up to 96 h after ischemia-reperfusion injury. These results revealed that MCP-1 via CCR2 signaling plays a key role in the pathogenesis of renal ischemia-reperfusion injury through infiltration and activation of macrophages, and it offers a therapeutic target for ischemia-reperfusion.
D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D015870:Gene Expression / Q000276:immunology; D005857:Germanium; D006098:Granulocytes / Q000166:cytology; D007369:Interferon Inducers / Q000494:pharmacology; D007668:Kidney / Q000502:physiology; D007683:Kidney Tubular Necrosis, Acute / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D009942:Organometallic Compounds / Q000494:pharmacology; D011422:Propionates; D012333:RNA, Messenger / Q000378:metabolism; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D007369:Interferon Inducers; D009942:Organometallic Compounds; D011422:Propionates; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D005857:Germanium; C066750:propagermanium; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse