Liraglutide protects against high-fat diet-induced kidney injury by ameliorating apoptosis.
Liraglutide protects against high-fat diet-induced kidney injury by ameliorating apoptosis.
复制标题
利拉鲁肽通过改善细胞凋亡来预防高脂饮食引起的肾损伤
DOI：
10.1530/ec-20-0294
复制
发表时间：
2020-10
影响因子：
2.9
通讯作者：
Cai M
中科院分区：
文献类型：
--
作者：
Liang R;Wang M;Fu C;Liang H;Deng H;Tan Y;Xu F;Cai M
肥胖与慢性肾脏疾病的发生和发展有关。新的证据表明胰高血糖素样肽-1受体激动剂可以减轻肾损害和蛋白尿。Sirtuin 1 （SIRT1）被认为是代谢相关肾病的关键调节因子。本文阐述了SIRT1在利拉鲁肽改善高脂肪饮食（HFD）诱导的肾损伤中的作用。雄性C57BL/6小鼠用HFD诱导肾损伤20周，再用利拉鲁肽治疗8周，观察其对肾脏的保护作用。此外，我们还研究了该药对SV40 - MES - 13 （SV40）小鼠系膜细胞的作用机制。利拉鲁肽治疗改善了hfd诱导的代谢紊乱，包括高血糖、体重增加和胰岛素抵抗。此外，肾脏重量、尿白蛋白/肌酐、肾脏形态学改变，如空泡小管、肾小球肿大、肾小球基底膜增厚和小管间质纤维化也显著改善。此外，利拉鲁肽处理小鼠肾脏中凋亡细胞和凋亡标志物下调。此外，SIRT1蛋白表达上调，而在代谢疾病中作为氧化应激和凋亡介质的硫氧还蛋白相互作用蛋白（TXNIP）被利拉鲁肽下调。在SV40细胞中，当SIRT1被敲低时，利拉鲁肽逆转高糖（30 mM）诱导的cleaved caspase-3上调的作用受到阻碍；利拉鲁肽对TXNIP的下调作用被阻断。利拉鲁肽可能通过激活SIRT1和抑制TXNIP途径抑制细胞凋亡，从而对代谢性肾损伤产生有益作用。
Obesity is associated with the development and progression of chronic kidney disease. Emerging evidence suggests that glucagon-like peptide-1 receptor agonist could reduce renal damage and albuminuria. Sirtuin 1 (SIRT1) was considered as a crucial regulator in metabolism-related kidney disease. Herein, the role of SIRT1 in liraglutide-ameliorated high-fat diet (HFD)-induced kidney injury was illustrated. Male C57BL/6 mice were fed HFD for 20 weeks to induce kidney injury that was then treated with liraglutide for 8 weeks to estimate its protective effect on the kidney. Also, the mechanism of the drug in SV40 MES 13 (SV40) mouse mesangial cells was elucidated. Liraglutide treatment ameliorated HFD-induced metabolic disorders, including hyperglycemia, increasing body weight, and insulin resistance. In addition, kidney weight, urine albumin-to-creatinine, and kidney morphological changes such as vacuolated tubules, glomerulomegaly, thickened glomerular basement membrane, and tubulointerstitial fibrosis were also significantly ameliorated. Furthermore, apoptotic cells and apoptosis markers were downregulated in the kidney of liraglutide-treated mice. In addition, the expression of SIRT1 protein was upregulated, whereas thioredoxin-interacting protein (TXNIP), which serves as a mediator of oxidative stress and apoptosis in metabolism disease, was downregulated by liraglutide. In SV40 cells, the effect of liraglutide on reversing the upregulation of cleaved caspase-3 induced by high glucose (30 mM) was hampered when SIRT1 was knocked down; also, the downregulation of TXNIP by liraglutide was blocked. Liraglutide might have a beneficial effect on metabolism-related kidney damage by inhibiting apoptosis via activation of SIRT1 and suppression of TXNIP pathway.