Dragon (repulsive guidance molecule RGMb) inhibits E-cadherin expression and induces apoptosis in renal tubular epithelial cells.
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-β 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.
From the Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
Wenjing
W
Liu
Xiaoling
X
Li
Yueshui
Y
Zhao
Xiao-Ming
XM
Meng
Chao
C
Wan
Baoxue
B
Yang
Hui-Yao
HY
Lan
Herbert Y
HY
Lin
Yin
Y
Xia
D000818:Animals; D017209:Apoptosis; D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal; D015687:Cell Hypoxia / Q000235:genetics; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014517:Ureteral Obstruction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D015820:Cadherins; D015816:Cell Adhesion Molecules, Neuronal; D058851:GPI-Linked Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C483497:Rgmb protein, mouse; C505409:Casp3 protein, mouse; D053148:Caspase 3
Apoptosis; Bone Morphogenetic Protein (BMP); Cell Death; E-cadherin; Epithelial Cell; Hypoxia; Kidney