Pyruvate kinase M2 activation maintains mitochondrial metabolism by regulating the interaction between HIF-1α and PGC-1α in diabetic kidney disease
Abstract Background Pyruvate kinase isoform M2 (PKM2) activation has been suggested as a potential protective mechanism against kidney injury by improving mitochondrial dysfunction and anaerobic glycolysis. However, the underlying molecular mechanisms are unclear. Herein, we have demonstrated that P...
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| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-07-01
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| Series: | Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s10020-025-01320-4 |
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| Summary: | Abstract Background Pyruvate kinase isoform M2 (PKM2) activation has been suggested as a potential protective mechanism against kidney injury by improving mitochondrial dysfunction and anaerobic glycolysis. However, the underlying molecular mechanisms are unclear. Herein, we have demonstrated that PKM2 activation alleviates HIF-1α-mediated suppression of PGC-1α in diabetic kidney disease (DKD) models. Methods In animal DKD study, db/db mice were intraperitoneally injected with TEPP-46, a PKM2 activator. In vitro, primary cultured renal tubular epithelial cells (RTECs) from C57BL/6 mice were exposed to high glucose (HG) conditions with and without TEPP-46. The interaction between HIF-1α and PGC-1α was investigated using HIF-1α overexpression and suppression. Results Our findings in db/db mice kidneys unveiled a reduced PKM2 activation, aberrant glycolysis, impaired fatty acid oxidation, and decreased mitochondrial mass, integrity, and function under diabetic conditions. These changes were accompanied by increased HIF-1α and decreased PGC-1α levels. Furthermore, diabetic kidney exhibited increased fibrosis and apoptosis markers. Notably, direct PKM2 activation by TEPP-46 treatment counteracted the perturbed energy metabolism, restored mitochondrial function, and reduced cell death. Similar effects were also observed in HG-treated RTECs upon TEPP-46 intervention. Mechanistically, our chromatin immunoprecipitation assay revealed that HIF-1α directly bound to the regulatory region of the Ppargc1a promoter, and this interaction was inversely dependent on PKM2 activation. Moreover, Hif1ɑ overexpression suppressed Ppargc1a and triggered aberrant energy metabolism, mitochondrial dysfunction, and apoptosis. These changes were reversed by HIF-1α suppression. Conclusion Our study highlights the role of PKM2 activation in restoring impaired mitochondrial metabolism and function by modulating HIF-1α and PGC-1α interactions in DKD. |
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| ISSN: | 1528-3658 |