Increasing extracellular matrix collagen level and MMP activity induces cyst development in polycystic kidney disease

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>We examined the role of type I collagen (collagen I) and membrane bound type 1 MMP (MT1-MMP) on cyst development using both <it>in vitro</it> 3 dimensional (3D) collagen gel culture and <it>in vivo</it> PCK rat model of PKD.</p> <p>Results</p> <p>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.</p> <p>Conclusions</p> <p>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.</p

Polycystic liver diseases: advanced insights into the molecular mechanisms

Polycystic liver diseases are genetic disorders characterized by progressive bile duct dilatation and/or cyst development. The large volume of hepatic cysts causes different symptoms and complications such as abdominal distension, local pressure with back pain, hypertension, gastro-oesophageal reflux and dyspnea as well as bleeding, infection and rupture of the cysts. Current therapeutic strategies are based on surgical procedures and pharmacological management, which partially prevent or ameliorate the disease. However, as these treatments only show short-term and/or modest beneficial effects, liver transplantation is the only definitive therapy. Therefore, interest in understanding the molecular mechanisms involved in disease pathogenesis is increasing so that new targets for therapy can be identified. In this Review, the genetic mechanisms underlying polycystic liver diseases and the most relevant molecular pathways of hepatic cystogenesis are discussed. Moreover, the main clinical and preclinical studies are highlighted and future directions in basic as well as clinical research are indicated