Dataset Information

Role of Parkin-mediated mitophagy in the protective effect of polydatin in sepsis-induced acute kidney injury.

ABSTRACT: BACKGROUND:We have reported that polydatin (PD) alleviates mitochondrial dysfunction in rat models of sepsis-induced acute kidney injury (SI-AKI), but the mechanism is not well understood. Here, we investigated the role of Parkin-mediated mitophagy in the protective effects of PD in SI-AKI in mice. METHODS:Sepsis was induced in the mice by caecal ligation and puncture. Mitophagy was determined by mitochondrial mass. NLRP3 inflammasome activation was determined by NLRP3, ASC and caspase-1. Mitophagy was blocked by treatment with mitochondrial division inhibitor-1 and Parkin knockout. KEY RESULTS:PD treatment increased the sepsis-induced loss of mitochondrial mass, indicating the upregulation of mitophagy. Furthermore, PD treatment mediated Parkin translocation from the cytoplasm to the mitochondria. This suggests that Parkin-mediated mitophagy is an underlying mechanism. This was confirmed by the suppression of PD-induced mitophagy in Parkin-/- mice and in mice that were treated with a mitophagy inhibitor. PD-induced Parkin translocation and mitophagy were blocked by inhibiting SIRT1; thus, activation of SIRT1 might be an important molecular mechanism that is triggered by PD. Additionally, PD treatment protected against sepsis-induced kidney injury. These effects were blocked by inhibition of Parkin-dependent mitophagy. Furthermore, PD also protected against mitochondrial dysfunction and mitochondria-dependent apoptosis, and the effect was blocked when Parkin-dependent mitophagy was inhibited. Finally, PD suppressed NLRP3 inflammasome activation that was also dependent on Parkin-mediated mitophagy. CONCLUSIONS:These findings indicate that Parkin-mediated mitophagy is important for the protective effect of PD in SI-AKI, and the underlying mechanisms include the inhibition of mitochondrial dysfunction and NLRP3 inflammasome activation.

SUBMITTER: Gao Y

PROVIDER: S-EPMC7055075 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Role of Parkin-mediated mitophagy in the protective effect of polydatin in sepsis-induced acute kidney injury.

Gao Youguang Y Dai Xingui X Li Yunfeng Y Li Guicheng G Lin Xianzhong X Ai Chenmu C Cao Yuanyuan Y Li Tao T Lin Bo B

Journal of translational medicine 20200304 1

<h4>Background</h4>We have reported that polydatin (PD) alleviates mitochondrial dysfunction in rat models of sepsis-induced acute kidney injury (SI-AKI), but the mechanism is not well understood. Here, we investigated the role of Parkin-mediated mitophagy in the protective effects of PD in SI-AKI in mice.<h4>Methods</h4>Sepsis was induced in the mice by caecal ligation and puncture. Mitophagy was determined by mitochondrial mass. NLRP3 inflammasome activation was determined by NLRP3, ASC and ca ...[more]

PMID: 32131850

Similar Datasets

Project description:BackgroundTo study the protective effect of berberine (BBR) on cisplatin-induced acute kidney injury (AKI) and its effect on mitophagy.Methods(I) Male C57BL/6 mice aged 6-8 weeks were randomly divided into control group (saline), cisplatin group (cisplatin), and cisplatin + BBR (5, 10 mg/kg) groups. In the cisplatin group and BBR groups, mice were injected intraperitoneally with 15 mg/kg of cisplatin. Mice in BBR groups were given BBR at 72, 48, 24, 0.5 h before and 24, 48 h after cisplatin injection. Mice were sacrificed 72 h after cisplatin injection, and blood were collected for detecting serum creatinine (SCr) and blood urea nitrogen (BUN) levels. Kidneys were collected for detecting protein expression levels of Kidney injury molecule 1 (KIM-1), LC3 II/LC3 I, p62, PINK 1, Parkin in the renal tissue by Western blotting. The pathological changes in renal tissues were observed using periodic acid-Schiff (PAS) staining. (II) Renal tubular epithelial cells (RTECs) were pretreated with different concentrations (1, 2, and 4 µM) of BBR, and then incubated with cisplatin. Changes in autophagy proteins LC3 II/LC3 I, p62, PINK 1, and Parkin were detected by Western blotting, and changes in cellular reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were detected by flow cytometry.Results(I) Mice treated with BBR at dosage of 5 and 10 mg/kg for 6 days showed significant reduction in SCr and BUN compared to that in mice treated with cisplatin. PAS staining and immunohistochemistry showed that BBR ameliorated cisplatin-induced nephrotoxicity and reduced cisplatin-induced increase in protein expression levels of KIM-1. Compared to cisplatin-treated mice, the mice treated with BBR showed increased LC3 II/LC3 I, PINK 1, and Parkin, and decreased p62 protein expression. (II) Compared to cisplatin-incubated RTECs, cells pretreated with BBR for 24 h exhibited increased protein expressions of LC3 II/LC3 I, PINK1, and Parkin and decreased protein expression of p62. BBR reversed cellular ROS and cell MMP level induced by cisplatin.ConclusionsBBR plays a protective role in cisplatin-induced AKI by up-regulating mitophagy in RTECs.

Project description:Background: Acute kidney injury (AKI) portends worse prognosis following sepsis, with limited available interventions. Host iron acquisition by pathogens and systemic inflammatory response are key events in the pathogenesis of sepsis. In sepsis, hepcidin induces iron sequestration to limit iron availability to pathogens. Hepcidin is also known to limit inflammation. Since its role in pathophysiology of sepsis-associated AKI is unknown, we investigated the effect of exogenous hepcidin in endotoxin- and peritonitis-induced pathology and AKI. Methods: C57BL/6 mice were treated with saline or 50-100 µg of hepcidin, pre- and post-LPS injection, or cecal ligation and puncture (CLP, model of peritonitis). Splenectomized mice were challenged with LPS, with and without hepcidin. Mice were euthanized at 24 h after LPS injection and at different time points after CLP. Systemic inflammation and renal injury markers were assessed. Direct effect of hepcidin on renal tubular and endothelial cells was evaluated using endotoxin-induced cytotoxic serum. Role of heavy chain ferritin (H-ferritin) in mediating hepcidin-induced anti-inflammatory effect on LPS stimulated macrophages was evaluated with siRNA studies. Results: Twenty-four hours pretreatment with hepcidin significantly reduced LPS-induced AKI. Hepcidin ameliorated LPS-induced increase in serum TNFα and renal Cox-2, and prevented loss in PGC1α and cytochrome c oxidase activity. This was associated with reduced glomerular injury and preserved mitochondrial structure. Hepcidin did not exert direct protection on the renal parenchymal cells but reduced endotoxin-induced serum cytotoxicity to mitigate renal injury. Splenectomy reduced LPS-induced early inflammation and AKI, independent of hepcidin, indicating the importance of systemic inflammation. Higher splenic H-ferritin in hepcidin-treated animals was associated with reduced splenocytes apoptosis and inflammation. Hepcidin reduced LPS-induced IL-6 secretion in macrophages in H-ferritin dependent manner. Hepcidin significantly reduced CLP-induced AKI, and mortality (20% hepcidin treated vs 80% PBS treated). Importantly hepcidin reduced bacteremia and AKI even when administered after onset of sepsis. Conclusion: We demonstrate a protective role of hepcidin in endotoxin- and peritonitis-induced pathologies and AKI, exerted primarily through its anti-inflammatory effects, and antibacterial property. Macrophage H-ferritin plays an important role in hepcidin-mediated protection against endotoxin-induced inflammation. We uncover a novel prophylactic and therapeutic role of hepcidin in sepsis-associated bacteremia, AKI, and mortality.

Dataset Information

Role of Parkin-mediated mitophagy in the protective effect of polydatin in sepsis-induced acute kidney injury.

Publications

Role of Parkin-mediated mitophagy in the protective effect of polydatin in sepsis-induced acute kidney injury.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets