2. Academic Validation
  3. LIGHT deficiency aggravates cisplatin-induced acute kidney injury by upregulating mitochondrial apoptosis

LIGHT deficiency aggravates cisplatin-induced acute kidney injury by upregulating mitochondrial apoptosis

  • Int Immunopharmacol. 2020 Dec;89(Pt A):106999. doi: 10.1016/j.intimp.2020.106999.
Yan Yang 1,  Li Meng 2,  Shun Wu 3,  You Li 4,  Yu Zhong 2,  Feng Xu 5,  Xiao-Cui Zhou 6,  Gui-Qing Li 5,  Gui-Lian Xu 7,  Kan-Fu Peng 8
Affiliations

Affiliations

  • 1 Department of Nephrology, First Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China; Department of Immunology, Army Medical University (Third Military Medical University), Chongqing 400038, China; Department of Intensive Care Medicine, Third Affiliated Hospital (Daping Hospital), Army Medical University (Third Military Medical University), Chongqing 400042, China.
  • 2 Department of Nephrology, First Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China.
  • 3 Department of Nephrology, Huaihai Hospital affiliated with Xuzhou Medical University, Xuzhou 221004, China.
  • 4 Department of Intensive Care Medicine, Third Affiliated Hospital (Daping Hospital), Army Medical University (Third Military Medical University), Chongqing 400042, China.
  • 5 Department of Immunology, Army Medical University (Third Military Medical University), Chongqing 400038, China.
  • 6 Department of Intensive Care Medicine, First Affiliated Hospital, Chongqing Medical and Pharmaceutical College, Chongqing 400006, China.
  • 7 Department of Immunology, Army Medical University (Third Military Medical University), Chongqing 400038, China. Electronic address: xuguilian@tmmu.edu.cn.
  • 8 Department of Nephrology, First Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China. Electronic address: 392906786@qq.com.
PMID: 33045563 DOI: 10.1016/j.intimp.2020.106999
Abstract

Cisplatin is widely used as a chemotherapeutic agent for treating patients with solid tumors. The most common side effect of cisplatin treatment is nephrotoxicity. Recent studies have shown that mitochondrial apoptotic pathways are involved in cisplatin-induced acute kidney injury (Cis-AKI). LIGHT, the 14th member of the tumor necrosis factor superfamily (TNFSF14), was found to induce Apoptosis of certain types of tumor cells. So far, a link between LIGHT and Cis-AKI has not been reported. In this study, we observed that expression of LIGHT and its receptors HVEM and LTβR was increased in kidney tissues of mice after cisplatin treatment. LIGHT deficiency aggravated kidney injury, as evidenced by more severe tubular injury; remarkably increased levels of serum creatinine (Scr), blood urea nitrogen (BUN), and both kidney injury molecule-1 (KIM-1) and inflammatory cytokine mRNAs in renal tissues. Moreover, in the renal tissues of LIGHT KO mice, cisplatin-induced mitochondrion injury and the levels of the pro-apoptotic molecules Bax, Cytochrome C (Cyt C), cleaved Caspase-3, and cleaved caspase-9 were dramatically increased; in contrast, the expression of anti-apoptotic molecule Bcl-2 was markedly reduced, compared to those in WT mice, suggesting that LIGHT deficiency accelerated cisplatin-induced mitochondrial Apoptosis of renal tubular cells in these mice. Accordingly, treatment with recombinant human LIGHT (rLIGHT) was shown to alleviate cisplatin-induced kidney injury in vivo. Similar results were observed after the human renal tubular epithelial cell line HK-2 cells exposure to rLIGHT stimulation, evidenced by the reduction in the mitochondrion dysfunction (as confirmed by the significant reduced oxidative stress and membrane potential changes) and in the percentage of cells Apoptosis. While blocking LIGHT with the soluble fusion protein LTβR-Ig or HVEM-Ig accelerated the HK-2 cells Apoptosis. In conclusion, LIGHT deficiency aggravates Cis-AKI by promoting mitochondrial Apoptosis pathways.

Keywords

Acute kidney injury; Cisplatin; LIGHT; Mitochondrial apoptosis.

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