Email updates

Keep up to date with the latest news and content from BMC Nephrology and BioMed Central.

Open Access Highly Accessed Research article

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

Bin Liu12, Chenghai Li13, Zijuan Liu1, Zonghan Dai1 and Yunxia Tao1*

Author Affiliations

1 Internal Medicine, Texas Tech University Health Sciences Center, 79106 Amarillo, TX, USA

2 Institute of Life Science and Biology, Hunan University, Hunan, People’s Republic of China

3 Henan Provincial Centers for Disease Control and Prevention, Zhengzhou, People’s Republic of China

For all author emails, please log on.

BMC Nephrology 2012, 13:109  doi:10.1186/1471-2369-13-109

Published: 11 September 2012

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.

Keywords:
Collagen I; 3 dimensional (3D) collagen gel culture; Doxycycline; Matrix metalloproteinase; PCK rats; Polycystic kidney disease