Abstract
BackgroundPolycystic 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.MethodsWe 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.ResultsWe 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.ConclusionsOur 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.
Highlights
Polycystic Kidney Disease (PKD) kidneys exhibit increased extracellular matrix (ECM) collagen expression and metalloproteinases (MMPs) activity
We investigated the role of collagen I and membrane bound type 1 MMP (MT1-MMP) in cyst formation and growth using both in vitro 3 dimensional (3D) collagen I culture system and in vivo PCK rat model of PKD
Our results suggest that increased collagen expression and MMP activity in PKD kidneys may play a crucial role in renal cyst formation and enlargement
Summary
Polycystic Kidney Disease (PKD) kidneys exhibit increased extracellular matrix (ECM) collagen expression and metalloproteinases (MMPs) activity. Polycystic kidney disease (PKD) is the most common genetic disorder of the kidneys and is characterized by the progressive formation and enlargement of fluid-filled cysts. These cysts compress the normal adjacent parenchyma, leading to end-stage renal disease that requires dialysis and renal transplantation [1,2]. ADPKD is caused by a mutation in either the PKD1 or PKD2 genes and is manifested in adulthood with an incidence of 1:1000. ARPKD is caused by mutation in PKHD1 gene and is responsible for childhood cystic disease with an incidence of 1:20,000 [3,4]. Remarkable progress has been made in understanding the function of the PKD genes, the molecular and cellular mechanisms that lead to cyst formation and enlargement in PKD kidneys are still not fully understood
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