ADAM10 mediates ectopic proximal tubule development and renal fibrosis through Notch signalling

Bingjue Li, Chaohong Zhu, Lihua Dong, Jing Qin, Wenyu Xiang, Alan J. Davidson, Shi Feng, Yucheng Wang, Xiujin Shen, Chunhua Weng, Cuili Wang, Tingting Zhu, Lisha Teng, Junwen Wang, Christoph Englert, Jianghua Chen, Hong Jiang

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)274-289
Number of pages16
JournalJournal of Pathology
Volume252
Issue number3
DOIs
StatePublished - Nov 1 2020

Keywords

  • ADAM10
  • IgA nephropathy
  • Notch
  • chlorpyrifos
  • kidney development
  • proximal tubules
  • renal fibrosis

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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