4.8 Article

RGMb protects against acute kidney injury by inhibiting tubular cell necroptosis via an MLKL- dependent mechanism

出版社

NATL ACAD SCIENCES
DOI: 10.1073/pnas.1716959115

关键词

acute kidney injury; necroptosis; RGMb; proximal tubular cells; MLKL

资金

  1. National Natural Science Foundation of China (NSFC)/Research Grants Council [N_CUHK432/12, 81261160507]
  2. CUHK [4054305]
  3. NSFC [81660120]
  4. Science Foundation of Department of Education of Yunnan Province [2016ZZX013]
  5. General Basic Research Scheme of Yunnan Provincial Department of Science and Technology [2017FB106]
  6. National Cancer Institute [P50CA101942]
  7. Deutsche Forschungsgemeinschaft [AN372/16-2, AN372/20-1, AN372/23-1, AN372/24-1, MU3906/1-1]
  8. General Research Fund (GRF) Grants [14121816, C7018-16G]

向作者/读者索取更多资源

Tubular cell necrosis is a key histological feature of acute kidney injury (AKI). Necroptosis is a type of programed necrosis, which is executed by mixed lineage kinase domain-like protein (MLKL) upon its binding to the plasma membrane. Emerging evidence indicates that necroptosis plays a critical role in the development of AKI. However, it is unclear whether renal tubular cells undergo necroptosis in vivo and how the necroptotic pathway is regulated during AKI. Repulsive guidance molecule (RGM)-b is a member of the RGM family. Our previous study demonstrated that RGMb is highly expressed in kidney tubular epithelial cells, but its biological role in the kidney has not been well characterized. In the present study, we found that RGMb reduced membrane-associated MLKL levels and inhibited necroptosis in cultured cells. During ischemia/reperfusion injury (IRI) or oxalate nephropathy, MLKL was induced to express on the apical membrane of proximal tubular (PT) cells. Specific knockout of Rgmb in tubular cells (Rgmb cKO) increased MLKL expression at the apical membrane of PT cells and induced more tubular cell death and more severe renal dysfunction compared with wild-type mice. Treatment with the necroptosis inhibitor Necrostatin-1 or GSK'963 reduced MLKL expression on the apical membrane of PT cells and ameliorated renal function impairment after IRI in both wild-type and Rgmb cKO mice. Taken together, our results suggest that proximal tubular cell necroptosis plays an important role in AKI, and that RGMb protects against AKI by inhibiting MLKL membrane association and necroptosis in proximal tubular cells.

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