Vol. 9, Issue 7, 1675-1682, July 1998

Expression of the Recessive Glomerulosclerosis Gene Mpv17 Regulates MMP-2 Expression in Fibroblasts, the Kidney, and the Inner Ear of Mice

Alexander Reuter,^* Andrea Nestl,^* Ralf M. Zwacka, Jan Tuckermann,^§ Rüdiger Waldherr, Eva-Maria Wagner,^¶ Matti Höyhtyä,^# Angela M. Meyer zum Gottesberge,^@ Peter Angel,^§ and Hans Weiher^*¶

 ^*Forschungszentrum Karlsruhe, Institute of Genetics, D-76021 Karlsruhe, Germany;  University of Pennsylvania, Institute for Human Gene Therapy, Philadelphia, Pennsylvania 19104;  ^§German Cancer Research Center, D-69120 Heidelberg, Germany;  Institute of Pathology, University of Heidelberg, D-69120 Heidelberg, Germany;  ^¶Institute for Diabetes Research, 80804 München, Germany;  ^#DiaBor Inc., FIN-90220 Oulu, Finland; and  ^@Department of Otorhinolaryngology, University of Düsseldorf, D-40225 Düsseldorf, Germany

The recessive mouse mutant Mpv17 is characterized by the development of early-onset glomerulosclerosis, concomitant hypertension, and structural alterations of the inner ear. The primary cause of the disease is the loss of function of the Mpv17 protein, a peroxisomal gene product involved in reactive oxygen metabolism. In our search of a common mediator exerting effects on several aspects of the phenotype, we discovered that the absence of the Mpv17 gene product causes a strong increase in matrix metalloproteinase 2 (MMP-2) expression. This was seen in the kidney and cochlea of Mpv17-negative mice as well as in tissue culture cells derived from these animals. When these cells were transfected with the human Mpv17 homolog, an inverse causal relationship between Mpv17 and MMP-2 expression was established. These results indicate that the Mpv17 protein plays a crucial role in the regulation of MMP-2 and suggest that enhanced MMP-2 expression might mediate the mechanisms leading to glomerulosclerosis, inner ear disease, and hypertension in this model.