CCR2 signaling contributes to ischemia-reperfusion injury in kidney.

Abstract

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.

• Authors: Kengo Furuichi, Takashi Wada, Yasunori Iwata, Kiyoki Kitagawa, Ken-Ichi Kobayashi, Hiroyuki Hashimoto, Yoshiro Ishiwata, Masahide Asano, Hui Wang, Kouji Matsushima, Motohiro Takeya, William A Kuziel, Naofumi Mukaida, Hitoshi Yokoyama
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 14 Issue 10 Pg. 2503-15 (Oct 2003) ISSN: 1046-6673 [Print] United States
• PMID: 14514728 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ccr2 protein, mouse
• Chemokine CCL2
• Interferon Inducers
• Organometallic Compounds
• Propionates
• RNA, Messenger
• Receptors, CCR2
• Receptors, Chemokine
• Germanium
• propagermanium
• Nitric Oxide Synthase
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse

Topics

• Animals
• Chemokine CCL2 (genetics)
• Chemotaxis, Leukocyte (immunology)
• Gene Expression (immunology)
• Germanium
• Granulocytes (cytology)
• Interferon Inducers (pharmacology)
• Kidney (physiology)
• Kidney Tubular Necrosis, Acute (metabolism)
• Macrophages (cytology, physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred ICR
• Nitric Oxide Synthase
• Nitric Oxide Synthase Type II
• Organometallic Compounds (pharmacology)
• Propionates
• RNA, Messenger (metabolism)
• Receptors, CCR2
• Receptors, Chemokine (metabolism)
• Reperfusion Injury (metabolism)
• Signal Transduction (physiology)