Platycodin D attenuates diabetic renal ischemia/reperfusion injury by enhancing mitophagy and suppressing MAPK/NF-κB signaling activation

  • Biochim Biophys Acta Mol Basis Dis. 2025 Aug 21;1871(8):168026. doi: 10.1016/j.bbadis.2025.168026.
Xuke Qin  1 ,  Jin Liu  2 ,  Xiaojie Zhao  1 ,  Lei Wang  3 ,  Xiuheng Liu  4 ,  Zhiyuan Chen  5
Affiliations
  • 1. Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China; Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.
  • 2. Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.
  • 3. Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China; Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China. Electronic address: [email protected].
  • 4. Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China; Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China. Electronic address: [email protected].
  • 5. Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China; Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China. Electronic address: [email protected].
PMID: 40848991 DOI: 10.1016/j.bbadis.2025.168026
Abstract

The global incidence of diabetes mellitus (DM) is rapidly rising, and DM worsens renal ischemia/reperfusion (I/R) injury, a major cause of high-mortality acute kidney injury (AKI). Therefore, preventing renal I/R injury in DM is crucial. Platycodin D (PD), a compound from Platycodon grandiflorum roots, is known to activate AMP-activated protein kinase (AMPK). Numerous studies have demonstrated that AMPK activation has protective effects in diabetes mellitus (DM) and ischemia/reperfusion (I/R) injury. However, the impact of PD on renal I/R injury in DM and its underlying mechanisms remain unclear. Our experiments revealed that PD treatment via gavage significantly alleviated kidney tissue damage and cell Apoptosis in diabetic renal I/R injury. Additionally, PD reduced Reactive Oxygen Species (ROS) levels, and transmission electron microscopy (TEM) indicated a notable discovery in mitophagosome formation. The expression levels of P-AMPK, light chain 3B (LC3B)-II, PTEN-induced putative protein kinase 1 (PINK1) and Parkin all increased under PD treatment, while sequestosome 1 (p62) level decreased. Importantly, AMPK antagonist Compound C (CC) abolished these effects. Additionally, our transcriptomic profiling revealed that PD treatment significantly suppressed MAPK/NF-κB signaling activation. Through functional rescue experiments, we mechanistically demonstrated that PD-mediated AMPK phosphorylation governs this regulatory axis. AMPK inhibition abolished PD's effects on both MAPK/NF-κB suppression, establishing AMPK activation as the upstream modulator. Overall, PD may reduce renal I/R injury in DM through AMPK/PINK1/Parkin-mediated Mitophagy and inhibiting MAPK/NF-κB pathway.

Keywords
Diabetes mellitus; Inflammation; Mitophagy; Platycodin D; Renal ischemia/reperfusion injury.
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