EXPRESSION OF THE RECESSIVE GLOMERULOSCLEROSIS GENE MPV17 REGULATES MMP-2 EXPRESSION IN FIBROBLASTS, THE KIDNEY, AND THE INNER-EAR OF MICE

The recessive mouse mutant Mpv17 is characterized by the development o f early-onset glomerulosclerosis, concomitant hypertension, and struct ural 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 med iator exerting effects on several aspects of the phenotype, we discove red that the absence of the Mpv17 gene product causes a strong increas e in matrix metalloproteinase 2 (MMP-2) expression. This was seen in t he kidney and cochlea of Mpv17-negative mice as well as in tissue cult ure cells derived from these animals. When these cells were transfecte d with the human Mpv17 homolog, an inverse causal relationship between Mpv17 and MMP-2 expression was established. These results indicate th at the Mpv17 protein plays a crucial role in the regulation of MMP-2 a nd suggest that enhanced MMP-2 expression might mediate the mechanisms leading to glomerulosclerosis, inner ear disease, and hypertension in this model.