ADAM10 mediates ectopic proximal tubule development and renal fibrosis through Notch signalling.
ADAM10 mediates ectopic proximal tubule development and renal fibrosis through Notch signalling.
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ADAM10 通过 Notch 信号介导异位近曲小管发育和肾纤维化
DOI：
10.1002/path.5517
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发表时间：
2020-11
期刊：
影响因子：
--
通讯作者：
Jiang H
中科院分区：
文献类型：
--
作者：
Li B;Zhu C;Dong L;Qin J;Xiang W;Davidson AJ;Feng S;Wang Y;Shen X;Weng C;Wang C;Zhu T;Teng L;Wang J;Englert C;Chen J;Jiang H
宫内发育紊乱会增加患肾脏疾病的风险。各种研究报道Notch信号在肾脏发育和肾脏疾病中起着重要作用。一个解体素和金属蛋白酶结构域10 (ADAM10)， Notch通路的上游蛋白酶，也被报道参与肾纤维化。然而，ADAM10如何与Notch通路相互作用并导致肾纤维化尚不完全清楚。在这项研究中，我们使用产前毒死蜱（CPF）暴露小鼠模型，研究了ADAM10/Notch轴在肾脏发育和纤维化中的作用。我们发现，产前CPF暴露小鼠出现Adam10、Notch1和Notch2的过表达，并导致Six2+肾元祖细胞过早耗尽和胚胎肾近端小管（PTs）异位形成。由于ADAM10/Notch的持续激活，这些异常表型变化在成熟肾脏中持续存在，并在成人中表现出加重的肾纤维化。最后，在IgA肾病患者中ADAM10和NOTCH2的表达均与肾间质纤维化程度呈正相关，而ADAM10表达升高与肾功能下降呈负相关（血清肌酐、胱抑素C和肾小球滤过率）。回归分析还表明，ADAM10表达是IgAN纤维化的独立危险因素。©2020作者。《病理学杂志》由John Wiley & Sons， Ltd.代表大不列颠和爱尔兰病理学会出版。
Disturbed intrauterine development increases the risk of renal disease. Various studies have reported that Notch signalling plays a significant role in kidney development and kidney diseases. A disintegrin and metalloproteinase domain 10 (ADAM10), an upstream protease of the Notch pathway, is also reportedly involved in renal fibrosis. However, how ADAM10 interacts with the Notch pathway and causes renal fibrosis is not fully understood. In this study, using a prenatal chlorpyrifos (CPF) exposure mouse model, we investigated the role of the ADAM10/Notch axis in kidney development and fibrosis. We found that prenatal CPF‐exposure mice presented overexpression of Adam10, Notch1 and Notch2, and led to premature depletion of Six2+ nephron progenitors and ectopic formation of proximal tubules (PTs) in the embryonic kidney. These abnormal phenotypic changes persisted in mature kidneys due to the continuous activation of ADAM10/Notch and showed aggravated renal fibrosis in adults. Finally, both ADAM10 and NOTCH2 expression were positively correlated with the degree of renal interstitial fibrosis in IgA nephropathy patients, and increased ADAM10 expression was negatively correlated with decreased kidney function evaluated by serum creatinine, cystatin C, and estimated glomerular filtration rate. Regression analysis also indicated that ADAM10 expression was an independent risk factor for fibrosis in IgAN. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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