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1 Medical Research Center, Klinikum Mannheim, University of Heidelberg, 68167 Mannheim; and 2 Institute for Anatomy and Cell Biology I, University of Heidelberg, 69120 Heidelberg, Germany
The expansion of cysts in polycystic kidneys bears several
similarities to the invasion of the extracellular matrix by benign tumors. We therefore hypothesized that cyst-lining epithelial cells
produce extracellular matrix-degrading metalloproteinases and that the
inhibition of these enzymes may represent a potential target for
therapeutic intervention. Using in situ hybridization, we first
analyzed the expression of membrane-type metalloproteinase 1 (MMP-14),
an essential matrix metalloproteinase, of its inhibitor TIMP-2, and of the cytokine transforming growth factor (TGF)-
2 in
the (cy/+) rat model of autosomal-dominant
polycystic kidney disease. Upregulated MMP-14 mRNA was predominantly
located in cyst-lining epithelia and distal tubules, whereas TIMP-2
mRNA was confined almost exclusively to fibroblasts. TGF-2, a
cytokine known to regulate the expression of matrix metalloproteinases and their inhibitors, was also expressed by cyst wall epithelia. We
then treated (cy/+) rats with the
metalloproteinase inhibitor batimastat for a period of 8 wk. The
treatment with the metalloproteinase inhibitor batimastat resulted in a
significant reduction of cyst number and kidney weight. Our study
suggests that metalloproteinase inhibitors represent a new therapeutic
tool against polycystic kidney disease, which should be applicable
independently of the background of the disease.
autosomal-dominant polycystic kidney disease; therapy; extracellular matrix; matrix metalloproteinase-14; tissue inhibitor of
metalloproteinases-2; transforming growth factor-2
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