title: A possible role for metalloproteinases in renal cyst development.
abstract: 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)-beta2 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-beta2, 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.
authors.affiliation: Medical Research Center, Klinikum Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Obermüller
authors.forename: N
authors.initials: N
authors.lastname: Morente
authors.forename: B
authors.initials: B
authors.lastname: Kränzlin
authors.forename: N
authors.initials: N
authors.lastname: Gretz
authors.forename: R
authors.initials: R
authors.lastname: Witzgall
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016891:Polycystic Kidney, Autosomal Dominant / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D011480:Protease Inhibitors / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013876:Thiophenes / Q000627:therapeutic use; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics; D053781:Transforming Growth Factor beta2
chemical_list: D011480:Protease Inhibitors; D012333:RNA, Messenger; D013876:Thiophenes; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; D019716:Tissue Inhibitor of Metalloproteinase-2; D010649:Phenylalanine; C080985:batimastat; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases