Fenofibrate reduces cisplatin-induced apoptosis by inhibiting the p53/Puma/Caspase-9 pathway and the MAPK/Caspase-8 pathway rather than by promoting autophagy in murine renal proximal tubular cells.
Fenofibrate reduces cisplatin-induced apoptosis by inhibiting the p53/Puma/Caspase-9 pathway and the MAPK/Caspase-8 pathway rather than by promoting autophagy in murine renal proximal tubular cells.
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非诺贝特通过抑制p53/Puma/Caspase-9通路和MAPK/Caspase-8通路而不是通过促进小鼠近端肾小管细胞自噬来减少顺铂诱导的细胞凋亡。
DOI：
10.1016/j.bbrep.2022.101237
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发表时间：
2022-07
影响因子：
2.7
通讯作者：
Iwano M
中科院分区：
文献类型：
--
作者：
Kimura H;Kamiyama K;Imamoto T;Takeda I;Masunaga S;Kobayashi M;Mikami D;Takahashi N;Kasuno K;Sugaya T;Iwano M
顺铂肾毒性的主要损害是近端小管细胞因线粒体和死亡受体途径的凋亡增加而受损，可通过适当促进自噬来减轻这种损害。非诺贝特是一种过氧化物酶体增殖体激活受体α (PPAR-α)激活剂，最近有报道称其可促进自噬并防止顺铂肾毒性，但其机制仅部分分析。在这里，这些假定的保护作用的详细机制在小鼠肾近端小管（mProx）细胞系中进行了研究。基于流式细胞术的非诺贝特减弱顺铂诱导的mProx细胞凋亡。在线粒体凋亡途径方面，该试剂通过降低p53、JNK和14-3-3的磷酸化、胞质和线粒体Puma的积累、细胞色素C向胞质的释放以及由此导致的胞质caspase-9的激活来降低顺铂刺激的caspase-3激活。非诺贝特还通过抑制MAPK和NFkB通路以及降低死亡受体凋亡通路的主要介质TNF-α、TL1A和Fas的基因表达，降低顺铂刺激的caspase -8的激活。非诺贝特在饥饿状态下促进mProx细胞的自噬，其定义为p62减少和LC3 II/I增加。使用3-MA抑制自噬进一步增加了基础和顺铂诱导的caspase-3和-8的激活，但对非诺贝特对caspase激活的抑制作用没有影响。总之，我们的研究表明，非诺贝特是通过抑制线粒体和死亡凋亡途径而不是通过促进自噬来减轻顺铂肾毒性的候选药物。非诺贝特减少顺铂诱导的mProx细胞凋亡。非诺贝特通过抑制p53/Puma/caspase-9通路降低caspase-3的激活。非诺贝特通过抑制MAPK/死亡受体途径降低caspase-8的激活。非诺贝特促进饥饿条件下mProx细胞的自噬。然而，自噬抑制不影响保护作用。
The main lesion of cisplatin nephrotoxicity is damage to proximal tubular cells due to increased apoptosis via the mitochondrial and death receptor pathways, which may be alleviated by appropriate promotion of autophagy. Fenofibrate, a peroxisome proliferator-activated receptor-alpha (PPAR-α) activator, is recently reported to promote autophagy as well as protect against cisplatin nephrotoxicity, although the mechanisms were only partially analyzed. Here, the detailed mechanisms of these putative protective effects were investigated in a murine renal proximal tubular (mProx) cell line. Fenofibrate attenuated cisplatin-induced apoptosis of mProx cells based on flow cytometry. As for the mitochondrial apoptotic pathway, the reagent reduced cisplatin-stimulated caspase-3 activation by decreasing the phosphorylation of p53, JNK, and 14-3-3, cytosolic and mitochondrial Puma accumulation, cytochrome C release to the cytosol, and resulting cytosolic caspase-9 activation. Fenofibrate also decreased cisplatin-stimulated activation of caspases-8 by suppressing MAPK and NFkB pathways and reducing the gene expression of TNF-α, TL1A, and Fas, main mediators of the death receptor apoptotic pathway. Autophagy defined by p62 reduction and an increase in LC3 II/I was promoted by fenofibrate in mProx cells under starvation. Autophagy inhibition using 3-MA further increased basal and cisplatin-induced caspase-3 and -8 activation, but had no influence on the inhibitory effects of fenofibrate on caspase activation. In conclusion, our study suggests fenofibrate to be a candidate agent to mitigate cisplatin nephrotoxicity by inhibiting the mitochondrial and death apoptotic pathways rather than by promoting autophagy. Fenofibrate reduced cisplatin-induced apoptosis in mProx cells. Fenofibrate reduced caspase-3 activation by inhibiting p53/Puma/caspase-9 pathways. Fenofibrate reduced caspase-8 activation by inhibiting MAPK/death receptor pathways. Fenofibrate promoted autophagy in mProx cells under starvation conditions. Autophagy inhibition, however, did not affect the protective effects.
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DOI：
10.5049/ebp.2014.12.2.55
发表时间：
2014-12
期刊：
Electrolyte & blood pressure : E & BP
影响因子：
--
作者：
Oh GS;Kim HJ;Shen A;Lee SB;Khadka D;Pandit A;So HS
通讯作者：
So HS
影响因子：
64.8
作者：
Lee, Jae Man;Wagner, Martin;Xiao, Rui;Kim, Kang Ho;Feng, Dan;Lazar, Mitchell A.;Moore, David D.
通讯作者：
Moore, David D.
影响因子：
19.6
作者：
Kaushal GP;Shah SV
通讯作者：
Shah SV
影响因子：
--
作者：
Ozkok A;Edelstein CL
通讯作者：
Edelstein CL
影响因子：
19.6
作者：
Wei, Q.;Dong, G.;Dong, Z.
通讯作者：
Dong, Z.