Dragon (Repulsive Guidance Molecule RGMb) Inhibits E-cadherin Expression and Induces Apoptosis in Renal Tubular Epithelial Cells

被引：29
作者：
Liu, Wenjing [1 ]
Li, Xiaoling [1 ]
Zhao, Yueshui [1 ]
Meng, Xiao-Ming [4 ,5 ]
Wan, Chao [1 ,2 ]
Yang, Baoxue [6 ,7 ]
Lan, Hui-Yao [4 ,5 ]
Lin, Herbert Y. [3 ]
Xia, Yin [1 ,2 ]
机构：
[1] Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Key Lab Regenerat Med,Minist Educ, Hong Kong, Hong Kong, Peoples R China
[2] Chinese Univ Hong Kong, Shenzhen Res Inst, Sch Biomed Sci Core Lab, Shenzhen 518057, Peoples R China
[3] Harvard Univ, Ctr Syst Biol,Med Sch, Massachusetts Gen Hosp,Program Membrane Biol, Program Anemia Signaling Res,Div Nephrol,Dept Med, Boston, MA 02114 USA
[4] Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Hong Kong, Hong Kong, Peoples R China
[5] Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China
[6] Peking Univ, Sch Basic Med Sci, Dept Pharmacol, Beijing 100191, Peoples R China
[7] Minist Educ, Key Lab Mol Cardiovasc Sci, Beijing 100191, Peoples R China
来源：
JOURNAL OF BIOLOGICAL CHEMISTRY | 2013年 / 288卷 / 44期
基金：
中国国家自然科学基金;
关键词：
MORPHOGENETIC PROTEIN CORECEPTOR; REGULATES HEPCIDIN EXPRESSION; FIBROSIS; KIDNEY; NEOGENIN; INJURY; RECEPTORS; INFLAMMATION; TRANSITION; MECHANISMS;
D O I：
10.1074/jbc.M113.517573
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Dragon is one of the three members of the repulsive guidance molecule (RGM) family, i.e. RGMa, RGMb (Dragon), and RGMc (hemojuvelin). We previously identified the RGM members as bone morphogenetic protein (BMP) co-receptors that enhance BMP signaling. Our previous studies found that Dragon is highly expressed in the tubular epithelial cells of mouse kidneys. However, the roles of Dragon in renal epithelial cells are yet to be defined. We now show that overexpression of Dragon increased cell death induced by hypoxia in association with increased cleaved poly(ADP-ribose) polymerase and cleaved caspase-3 levels in mouse inner medullary collecting duct (IMCD3) cells. Dragon also inhibited E-cadherin expression but did not affect epithelial-to-mesenchymal transition induced by TGF-beta in IMCD3 cells. Previous studies suggest that the three RGM members can function as ligands for the receptor neogenin. Interestingly, our present study demonstrates that the Dragon actions on apoptosis and E-cadherin expression in IMCD3 cells were mediated by the neogenin receptor but not through the BMP pathway. Dragon expression in the kidney was up-regulated by unilateral ureteral obstruction in mice. Compared with wild-type mice, heterozygous Dragon knock-out mice exhibited 45-66% reduction in Dragon mRNA expression, decreased epithelial apoptosis, and increased tubular E-cadherin expression and had attenuated tubular injury after unilateral ureteral obstruction. Our results suggest that Dragon may impair tubular epithelial integrity and induce epithelial apoptosis both in vitro and in vivo.
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收藏
页码：31528 / 31539
页数：12
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