Abstract
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.
Highlights
Dragon is expressed in kidney tubular epithelial cells
When Dragon expression was inhibited by 74.2% by siRNA targeting (Fig. 2E), hypoxia-induced cell viability was significantly increased (Fig. 2F). These results suggest that Dragon increases epithelial cell death/apoptosis induced by hypoxia
These results suggest that Dragon promotes ureteric obstruction (UUO)-induced renal tubular epithelial cell apoptosis in vivo
Summary
Dragon is expressed in kidney tubular epithelial cells. Results: Dragon inhibits E-cadherin expression and induces apoptosis in IMCD3 cells, and Dragonϩ/Ϫ mice exhibit increased E-cadherin expression and decreased apoptosis in injured renal tubules. Our previous studies found that Dragon is highly expressed in the tubular epithelial cells of mouse kidneys. Our previous studies showed that the Dragon protein is expressed in the epithelial cells of kidney tubules including collecting ducts, distal convoluted tubules, and thick ascending limbs and that Dragon enhances BMP4 signaling in tubular epithelial cells [6]. These data suggest that Dragon may play a role in kidney epithelial function. Compared with WT mice, heterozygous Dragon knock-out mice exhibited decreased cell apoptosis and increased E-cadherin expression in tubular epithelial cells and had attenuated tubular injury in obstructed kidneys. Our results have revealed previously unidentified biological roles for Dragon in renal tubular injury
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