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, ultimately leading to end-stage renal disease that requires dialysis and renal transplantation [1
]. The two major inherited forms of PKD are Autosomal Dominant PKD (ADPKD) and Autosomal Recessive PKD (ARPKD). ADPKD is caused by a mutation in either the PKD1
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
]. Although 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.
Growing evidence suggests that abnormal extracellular matrix (ECM) remodeling may represent a common pathway for cyst formation and development in ADPKD and ARPKD kidneys. Normal ECM remodeling is tightly regulated by dynamic synthesis and degradation of its components. This tight regulation is essential for proper morphogenesis during embryo development and for maintaining tissue and organ structure homeostasis in the adult [5
]. During kidney development, ECM undergoes active remodeling and the levels of both, collagens, the main components of ECM, and MMPs, the main enzymes that degrade ECM components, are dynamically regulated. In particular, MMP2, MMP9, and MT1-MMP have been shown to play an important role in regulating local ECM remodeling during ureteric bud (UB) branching morphogenesis in kidney development [7
Studies have shown that renal interstitial fibrosis, which is caused by excessive accumulation and deposition of collagens, is a characteristic feature of both ADPKD and ARPKD. There is a strong correlation between the progression of interstitial fibrosis and the progression of cystic disease [9
]. In addition, overexpression of ECM collagens has been observed in cultured PKD cells as well as in PKD kidneys of human patients and animal models [11
]. Finally, gene expression profiling of cystic kidney tissues from both human PKD patients and animal PKD models has shown that a large portion of upregulated genes encode for ECM proteins [15
MMPs are key enzymes in ECM remodeling and their overexpression is another characteristic feature of PKD kidneys. Among the MMP family proteins, MMP2, MMP9 and MT1-MMP are the main collagen degradation enzymes. It has been shown that the expressions of these specific MMPs are increased in both PKD patients and PKD animal models [17
]. MT1-MMP has been shown to play a unique role in modifying pericellular collagen microenvironment and in regulating pro-MMP2 and pro-MMP9 activation. In addition to its collagen degradation activity, MT1-MMP has also been shown to be a potent mitogen for cell proliferation [20
]. Increased cell proliferation and dynamic remodeling of the microenvironment is a prerequisite for cyst enlargement, suggesting that MT1-MMP may be a major contributor in cyst growth.
In the present study, we investigated the role of collagen I and MT1-MMP in cyst formation and growth using both in vitro 3D collagen I culture system and in vivo PCK rat model of PKD. First, our studies reveal that the initiation of cyst structures requires higher collagen levels than that required for the formation of tubule structures. Secondly, we find that MT1-MMP stimulates cell proliferation and cyst enlargement. Finally, we show that the treatment of PCK rats with doxycycline, an FDA approved pan-MMPs inhibitor, significantly inhibited cystic disease progression in polycystic kidneys. Taken together, our results suggest that increased collagen expression and MMP activity in PKD kidneys may play a crucial role in renal cyst formation and enlargement.