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

Yongjun Zhu,Feng Ye,Liangbao Zhong,Hongwang Cui,Guojun Li,Xiaoyan Li,Jie Lv,Jean-Claude Dussaule

doi:10.1371/journal.pone.0228385

Yongjun Zhu, Feng Ye + Show 6 more

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https://doi.org/10.1371/journal.pone.0228385

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Abstract

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.

Highlights

Chronic kidney disease (CKD) causes serious health problems[1] and affects approximately 8–16% of adults worldwide[2, 3]
We found that necroptosis mediated by receptor-interacting serine-threonine kinase 3 (RIP3) and mixed lineage kinase domain-like (MLKL) might play a more significant role than apoptosis in mediating the loss of renal tubular cells rather than glomerular cells death in rats subjected to subtotal nephrectomy (SNx), favoring the progression of tubulointerstitial fibrosis (TIF) and CKD[5, 6]
We showed that necroptotic cell death is a more significant cause of the loss of renal tubular cells in SNx rats than apoptosis [5]

Summary

Introduction

Chronic kidney disease (CKD) causes serious health problems[1] and affects approximately 8–16% of adults worldwide[2, 3]. Its prognosis depends mainly on the degree of renal tubulointerstitial fibrosis (TIF) rather than glomerular damage[4]. Exploring the mechanism of TIF has great significance for the early prevention and treatment of CKD. We found that necroptosis mediated by receptor-interacting serine-threonine kinase 3 (RIP3) and mixed lineage kinase domain-like (MLKL) might play a more significant role than apoptosis in mediating the loss of renal tubular cells rather than glomerular cells death in rats subjected to subtotal nephrectomy (SNx), favoring the progression of TIF and CKD[5, 6].

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