Midkine is involved in neutrophil infiltration into the tubulointerstitium in ischemic renal injury.
Midkine (MK) is a multifunctional heparin-binding protein and promotes migration of neutrophils, macrophages, and neurons. In the normal mouse kidney, MK is expressed in the proximal tubules. After renal ischemic reperfusion injury, its expression in proximal tubules was increased. Immediate increase of MK expression was found when renal proximal tubular epithelial cells in culture were exposed to 5 mM H(2)O(2). Histologically defined tubulointerstitial damage was less severe in MK-deficient (Mdk(-/-)) than in wild-type (Mdk(+/+)) mice at 2 and 7 days after ischemic reperfusion injury. Within 2 days after ischemic injury, inflammatory leukocytes, of which neutrophils were the major population, were recruited to the tubulointerstitium. The numbers of infiltrating neutrophils and also macrophages were lower in Mdk(-/-) than in Mdk(+/+) mice. Induction of macrophage inflammatory protein-2 and macrophage chemotactic protein-1, chemokines for neutrophils and macrophages, respectively, were also suppressed in Mdk(-/-) mice. Furthermore, renal tubular epithelial cells in culture expressed macrophage inflammatory protein-2 in response to exogenous MK administration. These results suggested that MK enhances migration of inflammatory cells upon ischemic injury of the kidney directly and also through induction of chemokines, and contributes to the augmentation of ischemic tissue damage.
Sato
W
W
Department of Internal Medicine III and Biochemistry, Nagoya University School of Medicine, Nagoya, Japan.
Kadomatsu
K
K
Yuzawa
Y
Y
Muramatsu
H
H
Hotta
N
N
Matsuo
S
S
Muramatsu
T
T
D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D054426:Chemokine CXCL2; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D003433:Crosses, Genetic; D016207:Cytokines; D004847:Epithelial Cells / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007249:Inflammation; D007511:Ischemia / Q000276:immunology* / Q000378:metabolism; D007668:Kidney / Q000098:blood supply*; D007687:Kidney Tubules, Proximal / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D007958:Leukocyte Count; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000078792:Midkine; D009392:Nephrectomy; D009504:Neutrophils / Q000502:physiology*; D015427:Reperfusion Injury / Q000276:immunology / Q000378:metabolism; D013268:Stimulation, Chemical; D013481:Superoxides / Q000378:metabolism
D002352:Carrier Proteins; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D016207:Cytokines; D013481:Superoxides; D000078792:Midkine; D006861:Hydrogen Peroxide