ABCA1 deficiency contributes to podocyte pyroptosis priming via the APE1/IRF1 axis in diabetic kidney disease.
ABCA1 deficiency contributes to podocyte pyroptosis priming via the APE1/IRF1 axis in diabetic kidney disease.
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DOI：
10.1038/s41598-023-35499-5
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发表时间：
2023-06-14
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
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作者：
在糖尿病肾病（DKD）的足细胞中，已发现ATP结合盒转运蛋白A1（ABCA1）表达降低，且半胱天冬酶 - 4介导的非经典炎性小体发挥作用。为探究这些通路之间的联系，我们对ABCA1稳定敲低的人足细胞（siABCA1）中与细胞焦亡相关的介质进行了评估，发现与对照足细胞相比，siABCA1中IRF1、半胱天冬酶 - 4、GSDMD、半胱天冬酶 - 1和IL1β的mRNA水平显著升高，且半胱天冬酶 - 4、GSDMD和IL1β的蛋白水平同样升高。在siABCA1足细胞中敲低IRF1可阻止半胱天冬酶 - 4、GSDMD和IL1β的升高。虽然抑制TLR4不会降低IRF1和半胱天冬酶 - 4的mRNA水平，但在siABCA1足细胞中APE1蛋白表达增加，且一种APE1氧化还原抑制剂可消除siABCA1诱导的IRF1和半胱天冬酶 - 4的表达。敲低RELA也可抵消细胞焦亡启动，但染色质免疫沉淀（ChIP）未显示在siABCA1足细胞中NFκB与IRF1启动子的结合增加。最后，在体内对APE1/IRF1/Casp1轴进行了研究。与野生型相比，BTBR ob/ob小鼠肾小球中APE1免疫荧光染色以及IRF1和半胱天冬酶11的mRNA水平升高。总之，足细胞中ABCA1缺乏导致APE1积累，这会减少转录因子，从而增加IRF1及IRF1靶炎性小体相关基因的表达，进而引发细胞焦亡启动。
Decreased ATP Binding Cassette Transporter A1 (ABCA1) expression and caspase-4-mediated noncanonical inflammasome contribution have been described in podocytes in diabetic kidney disease (DKD). To investigate a link between these pathways, we evaluated pyroptosis-related mediators in human podocytes with stable knockdown of ABCA1 (siABCA1) and found that mRNA levels of IRF1, caspase-4, GSDMD, caspase-1 and IL1β were significantly increased in siABCA1 compared to control podocytes and that protein levels of caspase-4, GSDMD and IL1β were equally increased. IRF1 knockdown in siABCA1 podocytes prevented increases in caspase-4, GSDMD and IL1β. Whereas TLR4 inhibition did not decrease mRNA levels of IRF1 and caspase-4, APE1 protein expression increased in siABCA1 podocytes and an APE1 redox inhibitor abrogated siABCA1-induced expression of IRF1 and caspase-4. RELA knockdown also offset the pyroptosis priming, but ChIP did not demonstrate increased binding of NFκB to IRF1 promoter in siABCA1 podocytes. Finally, the APE1/IRF1/Casp1 axis was investigated in vivo. APE1 IF staining and mRNA levels of IRF1 and caspase 11 were increased in glomeruli of BTBR ob/ob compared to wildtype. In conclusion, ABCA1 deficiency in podocytes caused APE1 accumulation, which reduces transcription factors to increase the expression of IRF1 and IRF1 target inflammasome-related genes, leading to pyroptosispriming.
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影响因子：
--
作者：
Ristola M;Arpiainen S;Saleem MA;Mathieson PW;Welsh GI;Lehtonen S;Holthöfer H
通讯作者：
Holthöfer H
影响因子：
5.6
作者：
Hartman GD;Lambert-Cheatham NA;Kelley MR;Corson TW
通讯作者：
Corson TW
影响因子：
10.6
作者：
Downs KP;Nguyen H;Dorfleutner A;Stehlik C
通讯作者：
Stehlik C
影响因子：
7.7
作者：
Merscher-Gomez S;Guzman J;Pedigo CE;Lehto M;Aguillon-Prada R;Mendez A;Lassenius MI;Forsblom C;Yoo T;Villarreal R;Maiguel D;Johnson K;Goldberg R;Nair V;Randolph A;Kretzler M;Nelson RG;Burke GW 3rd;Groop PH;Fornoni A;FinnDiane Study Group
通讯作者：
FinnDiane Study Group
影响因子：
15.9
作者：
Pedigo, Christopher E.;Ducasa, Gloria Michelle;Fornoni, Alessia
通讯作者：
Fornoni, Alessia