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Metformin Protects Against Acute Kidney Injury Induced by Lipopolysaccharide via Up-Regulating the MCPIP1/SIRT1
Wen-Long Zhang1,2, Long-Jun Zhang3, Piao Liang3
1The First Clinical Hospital, Xiangnan University, Chenzhou, 423000, Hunan, People's Republic of China.
Abstract:
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.
Insights
Metformin protects against acute kidney injury (AKI) caused by lipopolysaccharide (LPS). It works by up-regulating the MCPIP1/SIRT1 pathway, reducing inflammation and kidney damage.
Area of Science:
- Nephrology
- Pharmacology
- Immunology
Background:
- Acute kidney injury (AKI) is a critical condition with significant morbidity and mortality.
- Lipopolysaccharide (LPS) is a potent inducer of inflammation and AKI.
- Metformin, a common anti-diabetic drug, has shown potential protective effects in various injury models.
Purpose of the Study:
- To investigate the protective effects of metformin on LPS-induced AKI in mice.
- To elucidate the underlying molecular mechanisms involving the MCPIP1/SIRT1 signaling pathway and NF-κB.
Main Methods:
- BALB/C mice were subjected to LPS challenge and treated with varying doses of metformin.
- Kidney tissue histology and apoptosis were assessed using H&E staining and TUNEL assay.
- Serum biomarkers (BUN, KIM-1, Creatinine, TNF-α, IL-1β) and protein expressions (MCPIP1, SIRT1, NF-κB) were analyzed.
Main Results:
- LPS induced significant kidney damage, elevated serum biomarkers, increased apoptosis, and altered protein expressions.
- Metformin treatment ameliorated kidney dysfunction, reduced serum inflammatory markers, and decreased apoptosis.
- Metformin upregulated MCPIP1 and SIRT1 expression while downregulating NF-κB activation.
Conclusions:
- Metformin demonstrates a protective effect against LPS-induced AKI.
- The mechanism involves the activation of the MCPIP1/SIRT1 pathway, leading to the inhibition of NF-κB-mediated inflammation.
- Metformin holds therapeutic potential for managing AKI.
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