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 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.
Reuter
A
A
Forschungszentrum Karlsruhe, Institute of Genetics, D-76021 Karlsruhe, Germany.
Nestl
A
A
Zwacka
R M
RM
Tuckermann
J
J
Waldherr
R
R
Wagner
E M
EM
Höyhtyä
M
M
Meyer zum Gottesberge
A M
AM
Angel
P
P
Weiher
H
H
D000818:Animals; D002478:Cells, Cultured; D003051:Cochlea / Q000201:enzymology / Q000378:metabolism; D007758:Ear, Inner / Q000201:enzymology / Q000378:metabolism*; D004789:Enzyme Activation / Q000235:genetics; D004794:Enzyme Repression / Q000235:genetics; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism*; D018093:Gelatinases / Q000096:biosynthesis*; D005786:Gene Expression Regulation; D005808:Genes, Recessive; D005923:Glomerulosclerosis, Focal Segmental / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2; D008565:Membrane Proteins; D008666:Metalloendopeptidases / Q000096:biosynthesis*; D051379:Mice; D008817:Mice, Mutant Strains; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics*
D008565:Membrane Proteins; C065292:Mpv17 protein, mouse; D011506:Proteins; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2