The First Clinical Hospital, Xiangnan University, Chenzhou, 423000, Hunan, People's Republic of China.
Department of Medical Administration, the First People's Hospital of Chenzhou, Chenzhou, 423000, Hunan, People's Republic of China.
Biochem Genet. 2024 Dec;62(6):4591-4602. doi: 10.1007/s10528-024-10692-x. Epub 2024 Feb 12.
In the present study, we aimed to explore the effect and underlying mechanism of metformin on lipopolysaccharide (LPS)-induced acute kidney injury (AKI). A total of 24 BALB/C mice were randomly divided into four groups: control group, LPS group and metformin group (50 or 100 mg/kg). The histological changes and cell apoptosis in kidney tissues were detected by hematoxylin-eosin staining and terminal-deoxynucleotidyl transferase-mediated nick end labeling assay, respectively. Enzyme-linked immunosorbent assay was applied to determine serum levels of blood urea nitrogen (BUN), kidney injury molecule-1 (Kim-1), creatinine (Cre), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β). Western blotting analysis were carried out to confirm the expressions of monocyte chemotactic protein-inducible protein 1 (MCPIP1), silent information regulator sirtuin 1 (SIRT1), and NF-κB p65 (acetyl K310). Compared with the control group, the mice in LPS group had glomerular capillary dilatation, renal interstitial edema, tubular cell damage and apoptosis. The serum levels of BUN, KIM-1, Cre, TNF-α, and IL-1β in LPS group were significantly higher than those in control group. Moreover, LPS also elevated the expressions of MCPIP1 and NF-κB p65 (acetyl K310) but decreased the expression of SIRT1 in kidney tissues. However, metformin distinctly decreased LPS-induced renal dysfunction, the serum levels of BUN, KIM-1, Cre, TNF-α, and IL-1β. In addition, metformin markedly increased the expressions of MCPIP1 and SIRT1 but decreased the expression of NF-κB p65 (acetyl K310) in kidney tissues. Metformin prevented LPS-induced AKI by up-regulating the MCPIP1/SIRT1 signaling pathway and subsequently inhibiting NF-κB-mediated inflammation response.
在本研究中，我们旨在探讨二甲双胍对脂多糖（LPS）诱导的急性肾损伤（AKI）的作用及其潜在机制。将 24 只 BALB/C 小鼠随机分为四组：对照组、LPS 组和二甲双胍组（50 或 100mg/kg）。通过苏木精-伊红染色和末端脱氧核苷酸转移酶介导的缺口末端标记法分别检测肾组织的组织学变化和细胞凋亡。酶联免疫吸附试验用于测定血清中血尿素氮（BUN）、肾损伤分子 1（Kim-1）、肌酐（Cre）、肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）的水平。Western blot 分析用于确认单核细胞趋化蛋白诱导蛋白 1（MCPIP1）、沉默信息调节因子 SIRT1 和 NF-κB p65（乙酰化 K310）的表达。与对照组相比，LPS 组的小鼠肾小球毛细血管扩张、肾间质水肿、肾小管细胞损伤和凋亡。LPS 组的血清 BUN、KIM-1、Cre、TNF-α 和 IL-1β 水平明显高于对照组。此外，LPS 还上调了肾组织中 MCPIP1 和 NF-κB p65（乙酰化 K310）的表达，但降低了 SIRT1 的表达。然而，二甲双胍明显降低了 LPS 诱导的肾功能障碍，降低了血清 BUN、KIM-1、Cre、TNF-α 和 IL-1β 的水平。此外，二甲双胍显著增加了肾组织中 MCPIP1 和 SIRT1 的表达，降低了 NF-κB p65（乙酰化 K310）的表达。二甲双胍通过上调 MCPIP1/SIRT1 信号通路，进而抑制 NF-κB 介导的炎症反应，防止 LPS 诱导的 AKI。
