Deficiency of growth factor midkine exacerbates necrotizing glomerular injuries in progressive glomerulonephritis

Hiroshi Kojima, Tomoki Kosugi, Waichi Sato, Yuka Sato, Kayaho Maeda, Noritoshi Kato, Kiyonari Kato, Shinichiro Inaba, Takuji Ishimoto, Naotake Tsuboi, Seiichi Matsuo, Shoichi Maruyama, Yukio Yuzawa, Kenji Kadomatsu

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8 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)410-419
Number of pages10
JournalAmerican Journal of Pathology
Volume182
Issue number2
DOIs
Publication statusPublished - 01-02-2013

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

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    Kojima, H., Kosugi, T., Sato, W., Sato, Y., Maeda, K., Kato, N., Kato, K., Inaba, S., Ishimoto, T., Tsuboi, N., Matsuo, S., Maruyama, S., Yuzawa, Y., & Kadomatsu, K. (2013). Deficiency of growth factor midkine exacerbates necrotizing glomerular injuries in progressive glomerulonephritis. American Journal of Pathology, 182(2), 410-419. https://doi.org/10.1016/j.ajpath.2012.10.016