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

BMC Nephrology

Research Article

Zijuan Liu¹  Yunxia Tao¹  Zonghan Dai¹  Chenghai Li²  Bin Liu³ 

[1] Internal Medicine, Texas Tech University Health Sciences Center, 79106, Amarillo, TX, USA;Internal Medicine, Texas Tech University Health Sciences Center, 79106, Amarillo, TX, USA;Henan Provincial Centers for Disease Control and Prevention, Zhengzhou, China;Internal Medicine, Texas Tech University Health Sciences Center, 79106, Amarillo, TX, USA;Institute of Life Science and Biology, Hunan University, Hunan, China;

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

DOI  :  10.1186/1471-2369-13-109

 received in 2012-02-22, accepted in 2012-08-27,  发布年份 2012

来源: Springer

【 摘 要 】

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.

【 授权许可】

Unknown   
© Liu et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.