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  • Title: Metformin modulates mitochondrial autophagy in renal tubular epithelial injury induced by high glucose via the Keap1/Nrf2 pathway.
    Author: Sun D, Li H, Du Y, Chen Y, Yao L, Wang L.
    Journal: Mol Cell Biochem; 2024 Sep; 479(9):2483-2496. PubMed ID: 37831352.
    Abstract:
    The current study aimed to explore the role and underpinning molecular mechanisms of metformin in renal cellular injury induced by high glucose levels. Male C57BL/KsJ (db/db) and (db/m +) mice were utilized in this study. The experimental group was administered 1 mg/mL of metformin through drinking water. Renal tissues were harvested for hematoxylin and eosin (HE) staining, superoxide dismutase (SOD) activity detection, biochemical indices analysis, Western blotting, and qRT-PCR. HK-2 cells were utilized for Nrf2 siRNA transfection and to establish a high level of glucose-induced cell models. Metformin was administered at a concentration of 1 mmol/L in the experimental group. Cellular viability was assessed using CCK-8, whereas acridine orange (AO) staining and LC3-mitotracker co-localization staining were employed to evaluate autophagy. The expression of Nrf2, P21, LC3, PTEN-induced putative kinase 1 (PINK1), translocase of outer mitochondrial membrane 20 (TOMM20), and Kelch-like ECH-associated protein 1 (Keap1) were determined through Western blotting and qRT-PCR. Metformin mitigated renal tissue inflammatory damage in diabetic mice, as indicated by upregulated expression of Nrf2, PINK1, LC3, and TOMM20, and downregulated expression of Keap1 and P21. High level of glucose treatment in HK-2 cells resulted in decreased autophagy, and reduced expression of Nrf2, PINK1, LC3, and TOMM20 alongside elevated the expression of Keap1 and P21. Notably, metformin treatment partially counteracted these effects. Nrf2 knockdown intensified these phenomena in the high level of glucose-induced model. Protein-protein interaction network analysis indicated that Nrf2 could regulate the majority autophagy-related proteins via Keap1. Metformin modulates mitochondrial autophagy in high glucose-induced renal tubular epithelial senescence via the Keap1/Nrf2 pathway.
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