TY - JOUR
T1 - Midkine expression in the course of nephrogenesis and its role in ischaemic reperfusion injury
AU - Sato, Waichi
AU - Yuzawa, Yukio
AU - Kadomatsu, Kenji
AU - Tayasu, Tomoya
AU - Muramatsu, Hisako
AU - Muramatsu, Takashi
AU - Matsuo, Seiichi
PY - 2002
Y1 - 2002
N2 - 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.
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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U2 - 10.1093/ndt/17.suppl_9.52
DO - 10.1093/ndt/17.suppl_9.52
M3 - Article
C2 - 12386288
AN - SCOPUS:0036381379
SN - 0931-0509
VL - 17
SP - 52
EP - 54
JO - Nephrology Dialysis Transplantation
JF - Nephrology Dialysis Transplantation
IS - SUPPL. 9
ER -