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© The Rockefeller University Press, 0021-9525/1997//1363 $5.00
The Journal of Cell Biology, Volume 136, Number 6, , 1997 1363-1373

Article

Matrix Metalloproteinases MMP2 and MMP9 Are Produced in Early Stages of Kidney Morphogenesis but Only MMP9 Is Required for Renal Organogenesis In Vitro



Brigitte Lelongt*, Germain Trugnan{ddagger}, Gillian Murphy§, and Pierre M. Ronco*

* Institut National de la Santé et de la Recherche Médicale, Unité 64, Hôpital Tenon, Paris, France; {ddagger} 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

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.

Abbreviations used in this paper: APMA, p-aminophenylmercuric acetate; DBA, dolichos biflorus agglutinin; HPA, helix pomatia agglutinin; MMP, matrix metalloproteinase; TIMP, tissue inhibitor of metalloproteinase; rhTIMP, recombinant human TIMP.

Address all correspondence to Brigitte Lelongt, Unité INSERM 64, Hôpital Tenon, 4 rue de la Chine, 75020 Paris, France. Tel.: (33) 1-40-30-65-14. Fax: (33) 1-40-30-62-17. e-mail: brigitte.lelongt{at}tnn.ap-hop-paris.fr


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