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Published ahead of print on August 27, 2009
J Am Soc Nephrol 20: 2171-2180, 2009
© 2009 American Society of Nephrology
doi: 10.1681/ASN.2009030312
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BASIC RESEARCH

MMP9 Limits Apoptosis and Stimulates Branching Morphogenesis During Kidney Development

Catherine Arnould*,{dagger}, Martine Lelièvre-Pégorier*,{ddagger},§, Pierre Ronco*,{dagger},|| and Brigitte Lelongt*,{dagger}

*Université Pierre et Marie Curie University of Paris 06, Paris, France;
{dagger}Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche Scientifique 702, Paris, France;
{ddagger}Université Paris Descartes University of Paris 05, Paris, France;
§Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche Scientifique 872, Centre de Recherche des Cordeliers, Paris, France; and
||Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Paris, France

Correspondence: Dr. Brigitte Lelongt, INSERM UMR S 702, Hôpital Tenon, 4 rue de la Chine, 75970 Paris Cedex 20, France. Phone: +33-1-56-01-65-14; Fax: +33-1-56-01-65-12; E-mail: brigitte.lelongt{at}upmc.fr

Received for publication March 20, 2009. Accepted for publication June 10, 2009.

Early events in kidney organogenesis involve reciprocal interactions between the ureteric bud and the metanephric mesenchyme, which lead to remodeling of the extracellular matrix. This remodeling involves matrix metalloproteases (MMPs), but the specific roles of individual MMPs in kidney development are not completely understood. Here, we analyzed MMP9-deficient mice at the first step of kidney development and found that MMP9 deficiency delayed embryonic kidney maturation and increased apoptosis ex vivo by 2.5-fold. These early defects resulted in a 30% decrease in nephron number, a 20% decrease in adult kidney weight, and altered kidney function and morphology at 12 mo. The membrane form of stem cell factor (SCF) increased, whereas the activated form of the SCF receptor, c-kit, decreased in MMP9-deficient embryonic kidneys. In organotypic culture, MMP9-deficient kidneys failed to secrete SCF, and addition of recombinant SCF partially rescued both apoptosis and the branching defect. In conclusion, these data show that MMP9 protects mesenchymal cells from apoptosis during kidney development and stimulates ureteric bud branching morphogenesis, most likely by releasing the soluble form of SCF, suggesting that normal renal development requires MMP9.


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