The role of Dragon (RGMb) in kidney injury

• Other Authors: Liu, Wenjing (author.)
• Format: Others
• Language: English; Chinese
• Published: 2014
• Subjects: Kidneys > Diseases > Molecular aspects; Kidney Diseases > genetics
• Online Access: http://repository.lib.cuhk.edu.hk/en/item/cuhk-1290634

Dragon (RGMb) is one of the three repulsive guidance molecule (RGM) family members RGMa, RGMb (Dragon) and RGMc (hemojuvelin). RGM family members are glycophosphatidylinositol (GPI)-anchored membrane proteins. The three RGM proteins have been identified as co-receptors that enhance BMP-Smad signaling. Previous studies showed that 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. However, the biological roles of Dragon in the renal epithelial cells are yet to be defined. === We now showed that overexpression of Dragon inhibited E-Cadherin expression, but did not affect epithelial-to-mesenchymal transition (EMT) induced by TGF-β1 in mouse inner medullary collecting duct (IMCD3) cells. Dragon also increased cell death induced by hypoxia in association with increased cleaved PARP and cleaved Caspase-3 levels in IMCD3 cells. Dragon did not have any effect on the expression of inflammatory factors in IMCD3 cells. Previous studies suggest that the three RGM members can also 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 upregulated by unilateral ureteral obstruction (UUO) in mice. Compared with wild-type mice, heterozygous Dragon knockout mice exhibited 45-66% reduction in Dragon mRNA expression, decreased epithelial cell apoptosis, increased tubular E-Cadherin expression, and had attenuated tubular injury after UUO. UUO-induced renal fibrosis and inflammation did not change between wild-type mice and heterozygous Dragon knockout mice. Similar results were obtained in the model of ischemia-reperfusion kidney injury. Compared with wild-type mice, heterozygous Dragon knockout mice showed decreased epithelial cell apoptosis. Ischemia-induced renal fibrosis and inflammation did not change between wild-type mice and heterozygous Dragon knockout mice. === Our results suggest that Dragon may impair tubular epithelial integrity and induce epithelial cell apoptosis both in vitro and in vivo. === Dragon (又稱排斥導向分子b) 是排斥導向分子家族中的一員。這個家族包括排斥導向分子a，排斥導向分子b (又稱Dragon) 和排斥導向分子c (又稱血幼素) 三名成員。它們都是一種磷脂酰肌醇(GPI) 錨定蛋白。研究發現，這三種排斥導向分子都可以作為輔助受體來加強骨形成蛋白信號通路。我們之前的研究發現，Dragon在集合管、遠曲小管和髓袢升支粗段的上皮細胞內都有表達，同時Dragon增強腎小管上皮細胞中骨形成蛋白(BMP)4的信號轉導。但是，Dragon在腎小管上皮細胞中的生物學功能尚不清楚。 === 我們的研究結果表明，Dragon過量表達后降低腎內髓集合管上皮細胞中上皮型鈣粘素 (E-Cadherin) 的表達，但是不影響轉化生長因子-β1誘導的上皮細胞向間充質細胞的轉化。在低氧的條件下，Dragon促進腎內髓集合管上皮細胞的死亡并同時增加活化的多聚二磷酸腺苷酸核糖聚合酶（PARP）和半胱天冬酶3 (Caspase-3) 的量。但是Dragon對腎內髓集合管上皮細胞分泌的免疫因子沒有影響。之前的研究表明，neogenin是這三個導向排斥分子的受體。同樣在我們的研究中發現，Dragon是通過neogenin受體而不是骨形成蛋白信號通路來影響腎內髓集合管上皮細胞的死亡和E-Cadherin的表達。 === 單側輸尿管結扎手術后，在受損傷的小鼠腎臟中Dragon的表達升高。與野生型的小鼠相比，雜合型Dragon敲除小鼠中Dragon信使核糖核酸的表達下降了45-66%，腎小管上皮細胞的凋亡減少，腎小管E-Cadherin的表達升高。單側輸尿管結扎手術后野生型和雜合型Dragon敲除小鼠腎臟皆存在纖維化和炎症，但是二者沒有差異。缺血再灌注的小鼠模型實驗中得到相似的結果。與野生型的小鼠相比，雜合子Dragon敲除小鼠中腎小管上皮細胞凋亡的數目減少。同樣缺血再灌注手術后野生型和雜合子Dragon敲除小鼠腎臟都也存在纖維化和炎症，但二者沒有差異。 === 體內和體外實驗结果均表明，在腎臟損傷過程中Dragon可能損害腎小管上皮的完整性并促進腎小管上皮細胞的凋亡。 === Liu, Wenjing. === Thesis (Ph.D.)--Chinese University of Hong Kong, 2014. === Includes bibliographical references (leaves 192-212). === Abstracts also in Chinese. === Title from PDF title page (viewed on 03, October, 2016). === Detailed summary in vernacular field only. === Detailed summary in vernacular field only. === Detailed summary in vernacular field only. === Detailed summary in vernacular field only.