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

Research output: Contribution to journalArticle

7 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

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Glomerulonephritis
Intercellular Signaling Peptides and Proteins
Plasminogen Activator Inhibitor 1
Wounds and Injuries
Fibrin
Endothelial Cells
Glomerular Basement Membrane
Plasminogen Activators
Fibrinolysis
midkine
Cultured Cells
Messenger RNA
Antibodies

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

Kojima, Hiroshi ; Kosugi, Tomoki ; Sato, Waichi ; Sato, Yuka ; Maeda, Kayaho ; Kato, Noritoshi ; Kato, Kiyonari ; Inaba, Shinichiro ; Ishimoto, Takuji ; Tsuboi, Naotake ; Matsuo, Seiichi ; Maruyama, Shoichi ; Yuzawa, Yukio ; Kadomatsu, Kenji. / Deficiency of growth factor midkine exacerbates necrotizing glomerular injuries in progressive glomerulonephritis. In: American Journal of Pathology. 2013 ; Vol. 182, No. 2. pp. 410-419.
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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.",
author = "Hiroshi Kojima and Tomoki Kosugi and Waichi Sato and Yuka Sato and Kayaho Maeda and Noritoshi Kato and Kiyonari Kato and Shinichiro Inaba and Takuji Ishimoto and Naotake Tsuboi and Seiichi Matsuo and Shoichi Maruyama and Yukio Yuzawa and Kenji Kadomatsu",
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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, vol. 182, no. 2, pp. 410-419. https://doi.org/10.1016/j.ajpath.2012.10.016

Deficiency of growth factor midkine exacerbates necrotizing glomerular injuries in progressive glomerulonephritis. / Kojima, Hiroshi; Kosugi, Tomoki; Sato, Waichi; Sato, Yuka; Maeda, Kayaho; Kato, Noritoshi; Kato, Kiyonari; Inaba, Shinichiro; Ishimoto, Takuji; Tsuboi, Naotake; Matsuo, Seiichi; Maruyama, Shoichi; Yuzawa, Yukio; Kadomatsu, Kenji.

In: American Journal of Pathology, Vol. 182, No. 2, 01.02.2013, p. 410-419.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Deficiency of growth factor midkine exacerbates necrotizing glomerular injuries in progressive glomerulonephritis

AU - Kojima, Hiroshi

AU - Kosugi, Tomoki

AU - Sato, Waichi

AU - Sato, Yuka

AU - Maeda, Kayaho

AU - Kato, Noritoshi

AU - Kato, Kiyonari

AU - Inaba, Shinichiro

AU - Ishimoto, Takuji

AU - Tsuboi, Naotake

AU - Matsuo, Seiichi

AU - Maruyama, Shoichi

AU - Yuzawa, Yukio

AU - Kadomatsu, Kenji

PY - 2013/2/1

Y1 - 2013/2/1

N2 - 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.

AB - 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.

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