Angiotensin II triggers RIPK3-MLKL-mediated necroptosis by activating the Fas/FasL signaling pathway in renal tubular cells

• Published in: PloS one Vol. 15; no. 3; p. e0228385
• Main Authors: Zhu, Yongjun, Cui, Hongwang, Lv, Jie, Li, Guojun, Li, Xiaoyan, Ye, Feng, Zhong, Liangbao
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 05-03-2020; Public Library of Science (PLoS)
• Subjects: Angiotensin; Angiotensin II; Angiotensins; Apoptosis; Atrophy; Biochemistry; Biology and Life Sciences; Biotechnology industries; Cell death; Disruption; Epithelial cells; FasL protein; Fibrosis; Gene expression; Kidney diseases; Kidneys; Kinases; Laboratory animals; Medicine and Health Sciences; Morphology; Mortality; Necroptosis; Necrosis; Nephrology; Orthopedics; Proteins; Research and Analysis Methods; Signal transduction; Signaling; Tumor necrosis factor; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Tumors; United States; Massachusetts; China; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0228385

Our earlier studies proved that RIPK3-mediated necroptosis might be an important mode of renal tubular cell death in rats with chronic renal injury and the necroptotic cell death can be triggered by tumor necrosis factor-α (TNF-α) in vitro, but the triggering role of angiotensin II (AngII), which exerts notable effects on renal cells for the initiation and progression of renal tubulointerstitial fibrosis, is largely unknown. Here, we identified the presence of necroptotic cell death in the tubular cells of AngII-induced chronic renal injury and fibrosis mice and assessed the percentage of necroptotic renal tubular cell death with the disruption of this necroptosis by the addition of necrostatin-1 (Nec-1). Furthermore, the observation was further confirmed in HK-2 cells treated with AngII and RIPK1/3 or MLKL inhibitors. The detection of Fas and FasL proteins led us to investigate the contribution of the Fas/FasL signaling pathway to AngII-induced necroptosis. Disruption of FasL decreased the percentage of necroptotic cells, suggesting that Fas and FasL are likely key signal molecules in the necroptosis of HK-2 cells induced by AngII. Our data suggest that AngII exposure might trigger RIPK3-MLKL-mediated necroptosis in renal tubular epithelial cells by activating the Fas/FasL signaling pathway in vivo and in vitro.