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

Liu, Wenjing; Li, Xiaoling; Zhao, Yueshui; Meng, Xiao‐Ming; Wan, Chao; Yang, Baoxue; Lan, Hui‐Yao; Lin, Herbert Y.; Xia, Yin

doi:10.1074/jbc.m113.517573

Cited by 25 publications

(20 citation statements)

References 37 publications

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“…Tubular integrity is strongly correlated with nephron function and can serve as a histological surrogate of whole kidney function. 11,12 Cdh1 (E-cadherin) is an indicator of tubular cell integrity and polarity whose expression is lost with ongoing obstructive injury leading to loss of tubular architecture. 13 As expected for M. musculus there was progressive loss of Cdh1 expression with each time point after UUO compared to the contralateral normal kidney (Fig 2E,F).…”

Section: Uuo Injurymentioning

confidence: 99%

Scarless repair of acute and chronic kidney injury in African Spiny mice (Acomys cahirinus)

Wakenight³

et al. 2018

Preprint

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Solid organ fibrosis is a major burden on global health and medical care costs. Muroid rodents of the genus Acomys (African Spiny mice) are terrestrial mammals that evolved remarkable abilities to regenerate severe skin wounds without scar formation. However, whether scar-free wound repair in Acomys extends beyond skin to vital internal organs is not known. Here, we used two aggressive kidney injury models known to produce severe renal fibrosis and show that despite equivalent acute kidney injury, there was rapid restoration of nephron structure and function without fibrosis in Acomys compared to extensive fibrosis leading to renal failure in Mus musculus. These results suggest Acomys species have evolved genomic adaptations for wound healing that activate regenerative repair pathways not only in skin, but also in vital internal organs. Our findings have important implications for discovering a long-sought evolutionary solution to internal organ injury and regeneration.

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Section: Uuo Injurymentioning

confidence: 99%

Scarless repair of acute and chronic kidney injury in African Spiny mice (Acomys cahirinus)

Wakenight³

et al. 2018

Preprint

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Section: Rgma Rgmb and Rgmcmentioning

confidence: 99%

“…Studies in renal epithelial cells have revealed the potential of RGMb to down-regulate E-cadherin protein expression, a hallmark of the EMTresponse and to induce apoptosis, both being well-established responses to TGF-b (Liu et al 2013). Attempts to link RGMb function to the action of TGF-b have so far not provided positive results (Liu et al 2013). The RGMb homolog RGMa also acts as a BMP coreceptor and facilitates the selective association of BMP ligands to specific type II receptors, so that high RGMa expression selects for ActRII as the signaling receptor of BMP-2 and BMP-4, whereas low RGMa expression permits the same ligands to select for BMPRII as their signaling receptor (Xia et al 2007).…”

Section: Rgma Rgmb and Rgmcmentioning

confidence: 99%

Signaling Receptors for TGF-β Family Members

Heldin

Moustakas

2016

Cold Spring Harb Perspect Biol

580

498

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Transforming growth factor b (TGF-b) family members signal via heterotetrameric complexes of type I and type II dual specificity kinase receptors. The activation and stability of the receptors are controlled by posttranslational modifications, such as phosphorylation, ubiquitylation, sumoylation, and neddylation, as well as by interaction with other proteins at the cell surface and in the cytoplasm. Activation of TGF-b receptors induces signaling via formation of Smad complexes that are translocated to the nucleus where they act as transcription factors, as well as via non-Smad pathways, including the Erk1/2, JNK and p38 MAP kinase pathways, and the Src tyrosine kinase, phosphatidylinositol 3 0 -kinase, and Rho GTPases.

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“…Therefore, Dragon's effects on cell proliferation, which were found to be significant in cells cultured in high glucose concentrations [16], are presumably minor in our low glucose condition. Importantly, the reduction in cell apoptosis following Dragon overexpression or the increase in cell apoptosis upon Dragon knockdown was similar to the increase or decrease in cell viability that was observed following Dragon overexpression or knockdown respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Dragon is a co-receptor for bone morphogenetic protein (BMP) signaling, which plays essential roles in many biological processes [14, 15]. Our previous study demonstrated that Dragon inhibits E-cadherin expression in renal tubular cells of injured kidneys [16]. It also negatively regulates IL-6 expression in macrophages via the p38 and Erk1/2 MAPK pathways but not the Smad1/5/8 pathway [17].…”

Section: Introductionmentioning

confidence: 99%

Dragon (RGMb) induces oxaliplatin resistance in colon cancer cells

et al. 2016

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Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and a major cause of cancer mortality. Chemotherapy resistance remains a major challenge for treating advanced CRC. Therefore, the identification of targets that induce drug resistance is a priority for the development of novel agents to overcome resistance. Dragon (also known as RGMb) is a member of the repulsive guidance molecule (RGM) family. We previously showed that Dragon expression increases with CRC progression in human patients. In the present study, we found that Dragon inhibited apoptosis and increased viability of CMT93 and HCT116 cells in the presence of oxaliplatin. Dragon induced resistance of xenograft tumor to oxaliplatinin treatment in mice. Mechanistically, Dragon inhibited oxaliplatin-induced JNK and p38 MAPK activation, and caspase-3 and PARP cleavages. Our results indicate that Dragon may be a novel target that induces drug resistance in CRC.

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

Cited by 25 publications

References 37 publications

Scarless repair of acute and chronic kidney injury in African Spiny mice (Acomys cahirinus)

Scarless repair of acute and chronic kidney injury in African Spiny mice (Acomys cahirinus)

Signaling Receptors for TGF-β Family Members

Dragon (RGMb) induces oxaliplatin resistance in colon cancer cells

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