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* Institut National de la Santé et de la Recherche Médicale, Unité 64, Hôpital Tenon, Paris, France; We analyzed matrix metalloproteinase
(MMP) production by 11-d embryonic mouse kidneys
and the effects of these enzymes on subsequent renal
organogenesis. In vivo, immunolocalization of metalloproteinases by laser scanning confocal microscopy and
zymograms of kidney lysates showed that the mesenchyme of embryonic kidneys synthesized both MMP9
and MMP2 enzymes. In vitro, embryonic kidneys also
secreted both enzymes when cultured in a medium devoid of hormone, growth factor, and serum for 24 h
during which T-shaped branching of the ureter bud appeared. We then evaluated the role of MMP2 and
MMP9 in kidney morphogenesis by adding anti-MMP2
or anti-MMP9 IgGs to the culture medium of 11-d kidneys for 24 or 72 h. Although it inhibited activity of the
mouse enzyme, anti-MMP2 IgGs had no effect on kidney morphogenesis. In contrast, anti-MMP9 IgGs with
enzyme-blocking activity impaired renal morphogenesis, in a concentration-dependent manner, by inhibiting
T-shaped branching and further divisions of the ureter
bud. This effect was irreversible, still observed after inductive events and reproduced by exogenous tissue
inhibitor of metalloproteinase 1 (TIMP1), the natural
inhibitor of MMP9. These data provide the first demonstration of MMP9 and MMP2 production in vivo by 11-d
embryonic kidneys and further show that MMP9 is required in vitro for branching morphogenesis of the ureter bud.
Institut National de la Santé
et de la Recherche Médicale, CJF 96-07, Faculté Saint-Antoine, Paris, France; and § Strangeways Research Laboratory,
Cambridge, United Kingdom
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