title: Deficiency of growth factor midkine exacerbates necrotizing glomerular injuries in progressive glomerulonephritis.
abstract: Inflammatory cell infiltration and fibrin deposition play important roles in the development of crescentic glomerulonephritis (GN). In particular, activation of coagulation is an indispensable factor in crescent formation. However, the mechanisms underlying the pathogenesis of crescent formation have not been completely elucidated. We identified the growth factor midkine (MK) as a novel key molecule in the progression of crescentic GN induced by anti-glomerular basement membrane antibody. Despite the lack of significant differences in autologous and heterologous reactions, MK-deficient (Mdk(-/-)) mice unexpectedly showed a greater number of necrotizing glomerular injuries than wild-type (Mdk(+/+)) mice. Likewise, more tubulointerstitial damage was observed in Mdk(-/-) mice, and this damage positively correlated with glomerular injury. Plasminogen activator inhibitor (PAI)-1 was strongly induced in the injured glomerulus of Mdk(-/-) mice, particularly in crescents and endothelial cells. This enhanced PAI-1 production was associated with an increase in inflammatory cell infiltration and matrix deposition in the glomerulus and the interstitium of Mdk(-/-) mice. In line with these in vivo data, primary cultured endothelial cells derived from Mdk(-/-) mice exhibited higher PAI-1 mRNA expression on fibrin challenge and less fibrinolysis than Mdk(+/+) mice. In contrast, the expression of plasminogen activators was not affected. Our combined data suggest that MK leads to a blockade of PAI-1, which is closely associated with the suppression of crescentic GN.
authors.affiliation: Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kojima
authors.forename: Tomoki
authors.initials: T
authors.lastname: Kosugi
authors.forename: Waichi
authors.initials: W
authors.lastname: Sato
authors.forename: Yuka
authors.initials: Y
authors.lastname: Sato
authors.forename: Kayaho
authors.initials: K
authors.lastname: Maeda
authors.forename: Noritoshi
authors.initials: N
authors.lastname: Kato
authors.forename: Kiyonari
authors.initials: K
authors.lastname: Kato
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Inaba
authors.forename: Takuji
authors.initials: T
authors.lastname: Ishimoto
authors.forename: Naotake
authors.initials: N
authors.lastname: Tsuboi
authors.forename: Seiichi
authors.initials: S
authors.lastname: Matsuo
authors.forename: Shoichi
authors.initials: S
authors.lastname: Maruyama
authors.forename: Yukio
authors.initials: Y
authors.lastname: Yuzawa
authors.forename: Kenji
authors.initials: K
authors.lastname: Kadomatsu
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D054426:Chemokine CXCL2 / Q000378:metabolism; D003176:Complement C3 / Q000378:metabolism; D016207:Cytokines / Q000172:deficiency* / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005342:Fibrinolysis; D005921:Glomerulonephritis / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D007074:Immunoglobulin G / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000378:metabolism; D007677:Kidney Function Tests; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D000078792:Midkine; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011817:Rabbits
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054426:Chemokine CXCL2; D003176:Complement C3; C404915:Cxcl2 protein, mouse; D016207:Cytokines; D007074:Immunoglobulin G; D036341:Intercellular Signaling Peptides and Proteins; C582105:Mdk protein, mouse; D017395:Plasminogen Activator Inhibitor 1; D000078792:Midkine