中国病理生理杂志2025，Vol.41Issue(6)：1170-1180,11.DOI:10.3969/j.issn.1000-4718.2025.06.014
热量限制通过抑制铁死亡减轻叶酸诱导的小鼠急性肾损伤
Caloric restriction inhibits ferroptosis and alleviates folic acid-induced acute kidney injury in mice
摘要
Abstract
AIM:This study aims to explore the effects and underlying mechanisms of caloric restriction(CR)on folic acid(FA)-induced acute kidney injury(AKI)in mice.METHODS:An AKI model was established by in-traperitoneal injection of FA(250 mg/kg).(1)Twenty male C57BL/6J mice(20～25 g)were randomly assigned to 4 groups(n=5):sham+ad libitum(AL),FA+AL,sham+CR,and FA+CR.The mice in CR groups were subjected to a 66%reduction in daily food intake within a limited feeding window for 2 weeks,while those in AL groups had unrestricted access to food.All mice had free access to water,and their body weight changes were monitored throughout the experi-ment.(2)An additional set of twenty male C57BL/6J mice were divided into 4 groups(n=5):control,A769662,FA,and FA+A769662.The AMP-activated protein kinase(AMPK)agonist A769662(30 mg/kg)was administered intraperito-neally for 3 d prior to FA injection.(3)Modeling of tubule-specific AMPK knockout(RT-AMPK-CKO)mice followed the same protocol as wild-type C57BL/6J mice.Blood and kidney tissues were harvested 48 h after FA injection.Serum creati-nine(SCr)and blood urea nitrogen(BUN)levels were measured using an automatic biochemical analyzer.The kidney pa-thology was examined by HE staining.The malondialdehyde(MDA)level and the reduced/oxidized glutathione(GSH/GSSG)ratio were assessed using assay kits.The protein levels of p-AMPK,AMPK,and ferroptosis-related markers were evaluated by Western blot and immunohistochemistry.RESULTS:(1)After 2 weeks,CR significantly reduced body weight and increased p-AMPK level compared with AL group(P<0.05).(2)Compared with FA+AL group,the mice in FA+CR and FA+A769662 groups exhibited notably lowered SCr and BUN levels,reduced expression of kidney injury mole-cule-1 and neutrophil gelatinase-associated lipocalin,lowered tubular injury scores,decreased long-chain fatty acid-CoA ligase 4(FACL4)and 4-hydroxynonenal levels,restored glutathione peroxidase 4(GPX4)expression,decreased MDA level,and enhanced GSH/GSSG ratio(P<0.05).(3)In the FA-induced renal injury model,RT-AMPK-CKO mice showed no significant differences compared with wild-type mice(P>0.05).However,in the FA+CR model,RT-AMPK-CKO mice failed to exhibit renal protection,with increased lipid peroxidation,elevated MDA level,and reduced GSH/GSSG ratio(P<0.05).Furthermore,CR-induced down-regulation of FACL4 and up-regulation of GPX4 were significantly reversed in RT-AMPK-CKO mice(P<0.05).CONCLUSION:The CR attenuates FA-induced AKI in mice by activating AMPK and inhibiting ferroptosis.关键词
热量限制/铁死亡/叶酸/急性肾损伤/AMP活化蛋白激酶Key words
caloric restriction/ferroptosis/folic acid/acute kidney injury/AMP-activated protein kinase分类
临床医学引用本文复制引用
黄华,朱杰夫,夏瑶,宋志霞..热量限制通过抑制铁死亡减轻叶酸诱导的小鼠急性肾损伤[J].中国病理生理杂志,2025,41(6):1170-1180,11.基金项目
湖北省自然科学基金项目(No.2021CFB379) （No.2021CFB379）
宜昌市医疗卫生项目专项基金项目(No.A21-2-002) （No.A21-2-002）
