Dendrobine attenuates sepsis-associated acute kidney injury by promoting PINK1/PARKIN-mediated mitophagy
Chang Hu, Zhenying Wu, Tianlong Li, Jiachen Qu, Le Li, Bo Hu, Yiming Li, Zhiyong Peng
Abstract
Sepsis-associated acute kidney injury (SA-AKI) is a severe condition with high mortality rates and a lack of specific treatments. Dendrobine (DEN) has shown diverse pharmacological effects across different diseases. Nonetheless, its impact on SA-AKI remains unexplored. This study aimed to investigate DEN's therapeutic potential in SA-AKI and elucidate its mechanism of action. In vivo, SA-AKI models were induced through cecal ligation and puncture or lipopolysaccharide (LPS) administration, while in vitro model was established using LPS-stimulated HK-2 cells. We found that pre-treatment with DEN reduced levels of inflammation-related cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6), and improved kidney function in SA-AKI both in vitro and in vivo. RNA-seq analysis unveiled the critical role of mitophagy in DEN treatment for SA-AKI. We observed an initial increase in mitophagy-related proteins such as PINK1, PARKIN, and LC3B/A, peaking at 8 h post-LPS stimulation, followed by a subsequent decline. Additionally, we demonstrated that DEN upregulated the expression of mitophagy-associated proteins in both in vitro and in vivo SA-AKI models. Notably, we found that carbonyl cyanide 3-chlorophenylhydrazone (CCCP) increased LC3B/A levels in DEN treatment for SA-AKI, whereas Mdivi-1 counteracted the effect of DEN on PINK1, PARKIN, and LC3B/A. These findings demonstrated that DEN enhances mitophagy through the activation of PINK1/PARKIN-mediated pathways, thus mitigating SA-AKI.