Metformin Improves the Senescence of Renal Tubular Epithelial Cells in a High-Glucose State Through E2F1.
Metformin Improves the Senescence of Renal Tubular Epithelial Cells in a High-Glucose State Through E2F1.
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二甲双胍通过 E2F1 改善高糖状态下肾小管上皮细胞的衰老
DOI：
10.3389/fphar.2022.926211
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发表时间：
2022
影响因子：
5.6
通讯作者：
Guo, Bing
中科院分区：
文献类型：
--
作者：
Liang, Dan;Li, Zhiyang;Feng, Zhaowei;Yuan, Zhiping;Dai, Yunli;Wu, Xin;Zhang, Fan;Wang, Yuanyuan;Zhou, Yuxia;Liu, Lingling;Shi, Mingjun;Xiao, Ying;Guo, Bing
糖尿病肾病是慢性肾脏疾病的主要原因，也是糖尿病最常见的并发症。细胞衰老参与了糖尿病肾病的发病过程，但具体机制尚不清楚。细胞周期相关蛋白E2 F转录因子1（E2 F1）是E2 F转录因子家族的成员，在高血糖条件下细胞损伤中发挥关键作用。在这项研究中，我们探讨了二甲双胍是否通过细胞周期相关蛋白E2 F1改善高糖诱导的肾小管上皮细胞衰老和纤维化。在体内实验中，将敲除E2 F1基因的重组腺相关病毒（AAV-shE 2F 1）注射到16周龄db/db小鼠的尾静脉中，持续8周。对16周龄db/db小鼠连续给予二甲双胍（260 mg/kg/d）8周。同时设正常对照组（NC）和糖尿病模型组（DM）。体外培养小鼠肾小管上皮细胞（mRTECs）。将细胞随机分为以下组：正常糖（NG，含5.5 mmol/L葡萄糖），高糖组（HG，含30 mmol/L葡萄糖），NG/HG二甲双胍干预组（NG/HG + Met）、NG/HG阴性对照siRNA转染组（NG/HG + Control）、NG/HG E2 F1 siRNA转染组（NG/HG + siRNA E2 F1）、HG二甲双胍干预和过表达E2 F1质粒转染组（HG + Met +过表达-E2 F1）。采用Western blot、实时荧光定量PCR、免疫组化、免疫荧光等方法检测相关指标的表达。结果显示，E2 F1敲低或二甲双胍降低了DM组的肾纤维化程度、DNA损伤和细胞衰老;二甲双胍还降低了E2 F1的表达。如果E2 F1过表达，二甲双胍在延缓纤维化、减少DNA损伤和细胞衰老方面的作用可能会减弱。因此，二甲双胍通过下调E2 F1的表达来抑制高糖诱导的肾小管上皮细胞衰老和纤维化。
Diabetic kidney disease is a major cause of chronic kidney condition and the most common complication of diabetes. The cellular senescence participates in the process of diabetic kidney disease, but the specific mechanism is not yet clear. Cell cycle-related protein E2F transcription factor 1 (E2F1) is a member of the E2F transcription factor family, it plays a key role in cellular damage under HG conditions. In this study, we explored whether metformin improves a high-glucose-induced senescence and fibrosis of renal tubular epithelial cells through cell cycle-related protein E2F1. In the in vivo experiments, the recombinant adeno-associated virus (AAV-shE2F1) knockdown E2F1 gene was injected into the tail vein of 16-weeks-old db/db mice for 8 weeks. The 16-week-old db/db mice were administered metformin (260 mg/kg/d) continuously for 8 weeks. The normal control group (NC) and diabetic model group (DM) were set up simultaneously. Mice renal tubular epithelial cells (mRTECs) were cultured in vitro. The cells were randomly divided into the following groups: normal glucose (NG, containing 5.5 mmol/L glucose), high glucose group (HG, containing 30 mmol/L glucose), NG/HG metformin intervention group (NG/HG + Met), NG/HG negative control siRNA transfection group (NG/HG + Control), NG/HG E2F1 siRNA transfection group (NG/HG + siRNA E2F1), HG metformin intervention and overexpression E2F1 plasmid transfection group (HG + Met + overexpress-E2F1). The expression of related indexes were detected by Western blot, real-time polymerase chain reaction (PCR), immunohistochemistry, and immunofluorescence. The results showed that E2F1 knockdown or metformin reduces the degree of renal fibrosis, DNA damage, and cellular senescence in the DM group; metformin also reduced the expression of E2F1. If E2F1 was overexpressed, the effects of metformin in delaying fibrosis and reducing DNA damage and cellular senescence could be weakened. Thus, metformin alleviates high-glucose-induced senescence and fibrosis of renal tubular epithelial cells by downregulating the expression of E2F1.
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影响因子：
3
作者：
Kitada K;Nakano D;Ohsaki H;Hitomi H;Minamino T;Yatabe J;Felder RA;Mori H;Masaki T;Kobori H;Nishiyama A
通讯作者：
Nishiyama A
二甲双胍通过增强糖尿病肾病早期自噬来减轻肾小管间质纤维化
影响因子：
4.6
作者：
Wang F;Sun H;Zuo B;Shi K;Zhang X;Zhang C;Sun D
通讯作者：
Sun D
Optineurin介导的线粒体自噬保护糖尿病肾病肾小管上皮细胞免于加速衰老
影响因子：
9
作者：
Chen K;Dai H;Yuan J;Chen J;Lin L;Zhang W;Wang L;Zhang J;Li K;He Y
通讯作者：
He Y
影响因子：
5.6
作者：
Hsu SK;Cheng KC;Mgbeahuruike MO;Lin YH;Wu CY;Wang HD;Yen CH;Chiu CC;Sheu SJ
通讯作者：
Sheu SJ
影响因子：
11.1
作者：
Kirkland JL;Tchkonia T
通讯作者：
Tchkonia T