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

BMC Nephrology

Yunxia Tao³  Zonghan Dai³  Zijuan Liu³  Chenghai Li²  Bin Liu¹ 

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

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

Others  :  1083102
DOI  :  10.1186/1471-2369-13-109

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

【 摘 要 】

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.

【 授权许可】

   
2012 Liu et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 4.

【 参考文献 】

• [1]Wilson PD, Goilav B: Cystic disease of the kidney. Annu Rev Patho 2007, 2:341-368.
• [2]Pei Y, Watnick T: Diagnosis and screening of autosomal dominant polycystic kidney disease. Adv Chronic Kidney Dis 2010, 17(2):140-152.
• [3]Yoder BK, Mulroy S, Eustace H, Boucher C, Sandford R: Molecular pathogenesis of autosomal dominant polycystic kidney disease. Expert Rev Mol Med 2006, 8(2):1-22.
• [4]Al-Bhalal L, Akhtar M: Molecular basis of autosomal recessive polycystic kidney disease (ARPKD). Adv Anat Pathol 2008, 15(1):54-58.
• [5]Keeling J, Herrera GA: Human matrix metalloproteinases: characteristics and pathologic role in altering mesangial homeostasis. Microsc Res Tech 2008, 71(5):371-379.
• [6]Daley WP, Peters SB, Larsen M: Extracellular matrix dynamics in development and regenerative medicine. J Cell Sci 2008, 121:255-264.
• [7]Pohl M, Stuart OR, Sakurai H, Nigam SK: Branching morphogenesis during kidney development. Annu Rev Physiol 2000, 62:595-620.
• [8]Haas CS, Gleason B, Lin S, Tramonti G, Kanwar YS: Matrix metalloproteinases in renal development. Connect Tissue Res 2004, 45(2):73-85.
• [9]Ul Haque A, Moatasim A: Adult polycystic kidney disease: a disorder of connective tissue? Int J Clin Exp Pathol 2008, 1(1):84-90.
• [10]Okada H, Ban S, Nagao S, Takahashi H, Suzuki H, Neilson EG: Progressive renal fibrosis in murine polycystic kidney disease: an immunohistochemical observation. Kidney Int 2000, 58(2):587-597.
• [11]Wilson PD, Hreniuk D, Gabow PA: Abnormal extracellular matrix and excessive growth of human adult polycystic kidney disease epithelia. J Cell Physiol 1992, 150:360-369.
• [12]Candiano G, Gusmano R, Altieri P, Bertelli R, Ginevri F, Coviello DA, Sessa A, Caridi G, Ghiggeri GM: Extracellular matrix formation by epithelial cells from human polycystic kidney cysts in culture. Virchows Arch B Cell Pathol Incl Mol Pathol 1992, 63(1):1-9.
• [13]Ramasubbu K, Gretz N, Bachmann S: Increased epithelial cell proliferation and abnormal extracellular matrix in rat polycystic kidney disease. J Am Soc Nephrol 1998, 9(6):937-45.
• [14]Rankin CA, Itoh Y, Tian C, Ziemer DM, Calvet JP, Gattone VH: Matrix metalloproteinase-2 in a murine model of infantile-type polycystic kidney disease. J Am Soc Nephrol 1999, 10(2):210-217.
• [15]Schieren G, Rumberger B, Klein M, Kreutz C, Wilpert J, Geyer M, Faller D, Timmer J, Quack I, Rump LC, Walz G, Donauer J: Gene profiling of polycystic kidneys. Nephrol Dial Transplant 2006, 21(7):1816-1824.
• [16]Ebihara I, Nakamura T, Takahashi T, Yamamoto M, Tomino Y, Nagao S, Takahashi H: Altered extracellular matrix component gene expression in murine polycystic kidney. Renal Physiol. Biochem 1995, 18(2):73-80.
• [17]Schaefer L, Han X, Gretz N, Häfner C, Meier K, Matzkies F, Schaefer RM: Tubular gelatinase A (MMP-2) and its tissue inhibitors in polycystic kidney disease in the Han:SPRD rat. Kidney Int 1996, 49(1):75-81.
• [18]Bello-Reuss E, Holubec K, Rajaraman S: Angiogenesis in autosomal-dominant polycystic kidney disease. Kidney Int 2001, 60(1):37-45.
• [19]Harada H, Furuya M, Ishikura H, Shindo J, Koyanagi T, Yoshiki T: Expression of matrix metalloproteinase in the fluids of renal cystic lesions. J Urol 2002, 168(1):19-22.
• [20]Itoh Y, Seiki M: MT1-MMP: a potent modifier of pericellular microenvironment. J Cell Physiol 2006, 206(1):1-8.
• [21]Hotary KB, Allen ED, Brooks PC, Datta NS, Long MW, Weiss SJ: Membrane type I matrix metalloproteinase usurps tumor growth control imposed by the three-dimensional extracellular matrix. Cell 2003, 114(1):33-45.
• [22]Nyalendo C, Beaulieu E, Sartelet H, Michaud M, Fontaine N, Gingras D, Béliveau R: Impaired tyrosine phosphorylation of membrane type 1-matrix metalloproteinase reduces tumor cell proliferation in three-dimensional matrices and abrogates tumor growth in mice. Carcinogenesis 2008, 29(8):1655-1664.
• [23]Tao Y, Kim J, Yin Y, Zafar I, Falk S, He Z, Faubel S, Schrier RW, Edelstein CL: VEGF receptor inhibition slows the progression of polycystic kidney disease. Kidney Int 2007, 72(11):1358-1366.
• [24]Cowley BD, Gudapaty S, Kraybill AL, Barash BD, Harding MA, Calvet JP, Gattone VH, Cowley BD, Gudapaty S, Kraybill AL, Barash BD, Harding MA, Calvet JP, Gattone VH: Autosomal-dominant polycystic kidney disease in the rat. Kidney Int 1993, 43(3):522-534.
• [25]Masyuk TV, Masyuk AI, Torres VE, Harris PC, Larusso NF: Octreotide inhibits hepatic cystogenesis in a rodent model of polycystic liver disease by reducing cholangiocyte adenosine 3′,5′-cyclic monophosphate. Gastroenterology 2007, 132(3):1104-1116.
• [26]Nagao S, Nishii K, Katsuyama M, Kurahashi H, Marunouchi T, Takahashi H, Wallace DP: Increased water intake decreases progression of polycystic kidney disease in the PCK rat. J Am Soc Nephrol 2006, 17(8):2220-2227.
• [27]Togawa H, Nakanishi K, Mukaiyama H, Hama T, Shima Y, Sako M, Miyajima M, Nozu K, Nishii K, Nagao S, Takahashi H, Iijima K, Yoshikawa N: Epithelial-to-mesenchymal transition in cyst lining epithelial cells in an orthologous PCK rat model of autosomal-recessive polycystic kidney disease. Am J Physiol Renal Physiol. 2011, 300(2):F511-F520.
• [28]Karihaloo A, Kale S, Rosenblum ND, Cantley LG: Hepatocyte growth factor-mediated renal epithelial branching morphogenesis is regulated by glypican-4 expression. Mol Cell Biol 2004, 24(19):8745-8752.
• [29]Montesano R, Ghzili H, Carrozzino F, Rossier BC, Féraille E: CAMP-dependent chloride secretion mediates tubule enlargement and cyst formation by cultured mammalian collecting duct cells. Am J Physiol Renal Physiol. 2009, 296(2):F446-F457.
• [30]Golub LM, Ciancio S, Ramamamurthy NS, Leung M, McNamara TF: Low-dose doxycycline therapy Effect on gingival and crevicular fluid collagenase activity in humans. Journal of Periodontal Research 1990, 25(6):321-330.
• [31]Obermüller N, Morente N, Kränzlin B, Gretz N, Witzqall R: A possible role for metalloproteinases in renal cyst development. Am J Physiol Renal Physiol 2001, 280(3):F540-F550.