title: Increasing extracellular matrix collagen level and MMP activity induces cyst development in polycystic kidney disease.
abstract: BACKGROUND
  Polycystic Kidney Disease (PKD) kidneys exhibit increased extracellular matrix (ECM) collagen expression and metalloproteinases (MMPs) activity. We investigated the role of these increases on cystic disease progression in PKD kidneys.
  
  
  METHODS
  We examined the role of type I collagen (collagen I) and membrane bound type 1 MMP (MT1-MMP) on cyst development using both in vitro 3 dimensional (3D) collagen gel culture and in vivo PCK rat model of PKD.
  
  
  RESULTS
  We found that collagen concentration is critical in controlling the morphogenesis of MDCK cells cultured in 3D gels. MDCK cells did not form 3D structures at collagen I concentrations lower than 1 mg/ml but began forming tubules when the concentration reaches 1 mg/ml. Significantly, these cells began to form cyst when collagen I concentration reached to 1.2 mg/ml, and the ratios of cyst to tubule structures increased as the collagen I concentration increased. These cells exclusively formed cyst structures at a collagen I concentration of 1.8 mg/ml or higher. Overexpression of MT1-MMP in MDCK cells significantly induced cyst growth in 3D collagen gel culture. Conversely, inhibition of MMPs activity with doxycycline, a FDA approved pan-MMPs inhibitor, dramatically slowed cyst growth. More importantly, the treatment of PCK rats with doxycycline significantly decreased renal tubule cell proliferation and markedly inhibited the cystic disease progression.
  
  
  CONCLUSIONS
  Our data suggest that increased collagen expression and MMP activity in PKD kidneys may induce cyst formation and expansion. Our findings also suggest that MMPs may serve as a therapeutic target for the treatment of human PKD.
authors.affiliation: Internal Medicine, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.forename: Chenghai
authors.initials: C
authors.lastname: Li
authors.forename: Zijuan
authors.initials: Z
authors.lastname: Liu
authors.forename: Zonghan
authors.initials: Z
authors.lastname: Dai
authors.forename: Yunxia
authors.initials: Y
authors.lastname: Tao
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D018450:Disease Progression; D004285:Dogs; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism*; D052177:Kidney Diseases, Cystic / Q000209:etiology* / Q000378:metabolism*; D061985:Madin Darby Canine Kidney Cells; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D007690:Polycystic Kidney Diseases / Q000209:etiology* / Q000378:metabolism*; D051381:Rats
chemical_list: D003094:Collagen; D053511:Matrix Metalloproteinase 14