The PKM2 activator TEPP‐46 suppresses cellular senescence in hydrogen peroxide‐induced proximal tubular cells and kidney fibrosis in CD‐1db/db mice
ABSTRACT Aim/Introduction Senescence is a key driver of age‐related kidney dysfunction, including diabetic kidney disease. Oxidative stress activates cellular senescence, induces abnormal glycolysis, and is associated with pyruvate kinase muscle isoform 2 (PKM2) dysfunction; however, the mechanisms...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-04-01
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| Series: | Journal of Diabetes Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1111/jdi.14397 |
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| Summary: | ABSTRACT Aim/Introduction Senescence is a key driver of age‐related kidney dysfunction, including diabetic kidney disease. Oxidative stress activates cellular senescence, induces abnormal glycolysis, and is associated with pyruvate kinase muscle isoform 2 (PKM2) dysfunction; however, the mechanisms linking PK activation to cellular senescence have not been elucidated. We hypothesized that PKM2 activation by TEPP‐46 could suppress oxidative stress‐induced renal tubular cell injury and cellular senescence. Materials and Methods To investigate the effects of PKM2 activation on oxidative stress‐induced cellular senescence, we conducted β‐galactosidase staining and western blot analysis on human primary renal tubular cells (pRPTECs) treated with hydrogen peroxide with or without TEPP‐46. IL‐6 levels and glycolytic flux were measured. Cell viability and apoptosis were assessed via the MTS assay and caspase 3 cleavage. For in vivo experiments, we utilized CD‐1db/db mice, a fibrotic type 2 diabetes model, which exhibit kidney fibrosis. After 4 weeks of TEPP‐46 intervention, kidney fibrosis and the expression of senescence markers were analyzed. Results In pRPTECs, hydrogen peroxide increased the number of β‐galactosidase‐positive cells, the expression of senescence markers (p16, p21, p53), and p38 phosphorylation; co‐incubation with TEPP‐46 suppressed these alterations. Hydrogen peroxide reduced cell viability, induced apoptosis, mesenchymal alterations, and increased lactate production and IL‐6 secretion; co‐incubation with TEPP‐46 or a p38 inhibitor mitigated these effects. In CD‐1db/db mice, TEPP‐46 intervention suppressed apoptosis, fibrosis, and tended to reduce the levels of senescence‐associated molecules in the kidney. Conclusions PKM2 activation could be a molecular target for protection against senescence‐associated organ damage, including diabetic kidney disease. |
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| ISSN: | 2040-1116 2040-1124 |