Midkine expression in the course of nephrogenesis and its role in ischaemic reperfusion injury

Waichi Sato, Yukio Yuzawa, Kenji Kadomatsu, Tomoya Tayasu, Hisako Muramatsu, Takashi Muramatsu, Seiichi Matsuo

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Midkine (MK) is a multifunctional heparin-binding growth factor with migration-promoting activity for neutrophils, macrophages and neurones. Since enhanced expression of MK is observed in the tubular epithelial cells of the diseased kidney, it has been suggested that MK plays important roles in the pathogenesis of tubulointerstitial injury. The aim of this study was to determine the contribution of MK in nephrogenesis and in a murine model of ischaemic renal reperfusion injury (IRI). In the 11 day embryo, MK was expressed uniformly in both ureteric bud and metanephrogenic mesenchyme. The immature metanephros expressed both MK mRNA and MK protein more strongly than the mature metanephros. We studied the extent of tubulointerstitial injuries in MK wild-type [Mdk(+/+)] and knockout [Mdk(-/-)] mice 90 min after IRI. MK was expressed weakly in the proximal tubules in Mdk(+/+) mouse kidneys. After IRI, MK expression in proximal tubules increased and the new expression was observed in the distal tubules in Mdk(+/+) mice. Immediate induction of MK expression was observed when cultured tubular epithelial cells (TEpiCs) were exposed to 5 mM H2O2. Recombinant mouse MK (10 ng/ml) induced the increased expression of macrophage inflammatory protein 2 (MIP-2) mRNA in TEpiCs. Shortly after IRI, there were significantly fewer inflammatory leukocytes such as neutrophils and macrophages in Mdk(-/-) mice than in Mdk(+/+) mice. Marked up-regulation of monocyte chemoattractant protein 1 (MCP-1) and MIP-2 expression was detected in Mdk(+/+) mouse kidneys. Tubulointerstitial damage observed after IRI was significantly more suppressed in Mdk(-/-) mice than in Mdk(+/+) mice. These results suggest an important role for MK in the molecular cascade that regulates nephrogenesis. The present work also indicates that MK induces the chemotaxis of inflammatory leukocytes into the tubulointerstitium at least partly through the induction of MCP-1 and MIP-2, and that MK contributes to the aggravation of ischaemia-induced tubulointerstitial damage.

Original languageEnglish
Pages (from-to)52-54
Number of pages3
JournalNephrology Dialysis Transplantation
Volume17
Issue numberSUPPL. 9
Publication statusPublished - 09-10-2002
Externally publishedYes

Fingerprint

Reperfusion Injury
Kidney
Chemokine CXCL2
Chemokine CCL2
Epithelial Cells
midkine
Neutrophils
Macrophages
Leukocyte Chemotaxis
Messenger RNA
Wounds and Injuries
Kidney Diseases
Mesoderm
Knockout Mice
Heparin
Intercellular Signaling Peptides and Proteins
Leukocytes
Up-Regulation
Ischemia
Embryonic Structures

All Science Journal Classification (ASJC) codes

  • Nephrology
  • Transplantation

Cite this

Sato, W., Yuzawa, Y., Kadomatsu, K., Tayasu, T., Muramatsu, H., Muramatsu, T., & Matsuo, S. (2002). Midkine expression in the course of nephrogenesis and its role in ischaemic reperfusion injury. Nephrology Dialysis Transplantation, 17(SUPPL. 9), 52-54.
Sato, Waichi ; Yuzawa, Yukio ; Kadomatsu, Kenji ; Tayasu, Tomoya ; Muramatsu, Hisako ; Muramatsu, Takashi ; Matsuo, Seiichi. / Midkine expression in the course of nephrogenesis and its role in ischaemic reperfusion injury. In: Nephrology Dialysis Transplantation. 2002 ; Vol. 17, No. SUPPL. 9. pp. 52-54.
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Sato, W, Yuzawa, Y, Kadomatsu, K, Tayasu, T, Muramatsu, H, Muramatsu, T & Matsuo, S 2002, 'Midkine expression in the course of nephrogenesis and its role in ischaemic reperfusion injury', Nephrology Dialysis Transplantation, vol. 17, no. SUPPL. 9, pp. 52-54.

Midkine expression in the course of nephrogenesis and its role in ischaemic reperfusion injury. / Sato, Waichi; Yuzawa, Yukio; Kadomatsu, Kenji; Tayasu, Tomoya; Muramatsu, Hisako; Muramatsu, Takashi; Matsuo, Seiichi.

In: Nephrology Dialysis Transplantation, Vol. 17, No. SUPPL. 9, 09.10.2002, p. 52-54.

Research output: Contribution to journalArticle

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AU - Sato, Waichi

AU - Yuzawa, Yukio

AU - Kadomatsu, Kenji

AU - Tayasu, Tomoya

AU - Muramatsu, Hisako

AU - Muramatsu, Takashi

AU - Matsuo, Seiichi

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AB - Midkine (MK) is a multifunctional heparin-binding growth factor with migration-promoting activity for neutrophils, macrophages and neurones. Since enhanced expression of MK is observed in the tubular epithelial cells of the diseased kidney, it has been suggested that MK plays important roles in the pathogenesis of tubulointerstitial injury. The aim of this study was to determine the contribution of MK in nephrogenesis and in a murine model of ischaemic renal reperfusion injury (IRI). In the 11 day embryo, MK was expressed uniformly in both ureteric bud and metanephrogenic mesenchyme. The immature metanephros expressed both MK mRNA and MK protein more strongly than the mature metanephros. We studied the extent of tubulointerstitial injuries in MK wild-type [Mdk(+/+)] and knockout [Mdk(-/-)] mice 90 min after IRI. MK was expressed weakly in the proximal tubules in Mdk(+/+) mouse kidneys. After IRI, MK expression in proximal tubules increased and the new expression was observed in the distal tubules in Mdk(+/+) mice. Immediate induction of MK expression was observed when cultured tubular epithelial cells (TEpiCs) were exposed to 5 mM H2O2. Recombinant mouse MK (10 ng/ml) induced the increased expression of macrophage inflammatory protein 2 (MIP-2) mRNA in TEpiCs. Shortly after IRI, there were significantly fewer inflammatory leukocytes such as neutrophils and macrophages in Mdk(-/-) mice than in Mdk(+/+) mice. Marked up-regulation of monocyte chemoattractant protein 1 (MCP-1) and MIP-2 expression was detected in Mdk(+/+) mouse kidneys. Tubulointerstitial damage observed after IRI was significantly more suppressed in Mdk(-/-) mice than in Mdk(+/+) mice. These results suggest an important role for MK in the molecular cascade that regulates nephrogenesis. The present work also indicates that MK induces the chemotaxis of inflammatory leukocytes into the tubulointerstitium at least partly through the induction of MCP-1 and MIP-2, and that MK contributes to the aggravation of ischaemia-induced tubulointerstitial damage.

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Sato W, Yuzawa Y, Kadomatsu K, Tayasu T, Muramatsu H, Muramatsu T et al. Midkine expression in the course of nephrogenesis and its role in ischaemic reperfusion injury. Nephrology Dialysis Transplantation. 2002 Oct 9;17(SUPPL. 9):52-54.