RESUMO
Mitophagy removes dysfunctional mitochondria and is known to play an important role in the pathogenesis of several diseases; however, the role of mitophagy in acute respiratory distress syndrome (ARDS) remains poorly understood. While we have previously demonstrated that polydatin (PD) improves lipopolysaccharide (LPS)-induced ARDS, the specific mechanism remains unclear. In present study, we aimed to determine whether PD activates Parkin-dependent mitophagy to protect against LPS-induced mitochondria-dependent apoptosis and lung injury. To establish the ARDS model, C57BL/6 mice were intratracheally injected with LPS (5 mg/kg) in vivo and Beas-2B cells were exposured to 0.5 mM LPS in vitro. Our results indicate that PD facilitates Parkin translocation to mitochondria and promotes mitophagy in ARDS-challenged mice and LPS-treated Beas-2B cells. However, PD-induced mitophagy was suppressed in Parkin-/- mice and Parkin siRNA transfected cells, indicating that PD activates Parkin-dependent mitophagy. Furthermore, the protective effects of PD against LPS-induced mitochondria-dependent apoptosis and lung injury were suppressed when Parkin was depleted both in vivo and in vitro. The inhibition of mitophagy with mitophagy inhibitor mitochondrial division inhibitor-1 in vivo and silencing of autophagy-related gene 7 in vitro also blocked the protective effects mediated by PD. Our data suggest that Parkin-dependent mitophagy induced by PD provides protection against mitochondria-dependent apoptosis in ARDS.
Assuntos
Apoptose/efeitos dos fármacos , Glucosídeos/uso terapêutico , Mitofagia/efeitos dos fármacos , Síndrome do Desconforto Respiratório/tratamento farmacológico , Estilbenos/uso terapêutico , Ubiquitina-Proteína Ligases/metabolismo , Animais , Avaliação Pré-Clínica de Medicamentos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Fallopia japonica , Glucosídeos/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Fitoterapia , Síndrome do Desconforto Respiratório/metabolismo , Estilbenos/farmacologiaRESUMO
BACKGROUND: Mitochondrial injury is a major cause of sepsis-induced organ failure. Polydatin (PD), a natural polyphenol, demonstrates protective mitochondrial effects in neurons and arteriolar smooth muscle cells during severe shock. In this study, we investigated the effects of PD on renal tubular epithelial cell (RTEC) mitochondria in a rat model of sepsis-induced acute kidney injury. METHODS: Rats underwent cecal ligation and puncture (CLP) to mimic sepsis-induced acute kidney injury. Rats were randomly divided into sham, CLP + normal saline, CLP + vehicle, and CLP + PD groups. Normal saline, vehicle, and 30 mg/kg PD were administered at 6, 12, and 18 hours after CLP or sham surgery via the tail vein. Mitochondrial morphology, metabolism, and function in RTECs were then assessed. Serum cytokines, renal function, survival, and histologic changes in the kidney were also evaluated. RESULTS: CLP increased lipid peroxide content, lysosomal instability, and opening of the mitochondrial permeability transition pore and caused mitochondrial swelling. Moreover, mitochondrial membrane potential (ΔΨm) was decreased and ATP levels reduced after CLP. PD inhibited all the above effects. It also inhibited the inflammatory response, improved renal function, attenuated histologic indicators of kidney damage, and prolonged survival. CONCLUSIONS: PD protects RTECs against mitochondrial dysfunction and prolongs survival in a rat model of sepsis-induced acute kidney injury. These effects may partially result from reductions in interleukin-6 and oxidative stress.
Assuntos
Injúria Renal Aguda/tratamento farmacológico , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Glucosídeos/uso terapêutico , Túbulos Renais/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Sepse/tratamento farmacológico , Estilbenos/uso terapêutico , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Animais , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Células Epiteliais/patologia , Células Epiteliais/fisiologia , Glucosídeos/farmacologia , Túbulos Renais/patologia , Túbulos Renais/fisiologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/fisiologia , Mitocôndrias/fisiologia , Ratos , Ratos Sprague-Dawley , Sepse/complicações , Sepse/patologia , Estilbenos/farmacologiaRESUMO
BACKGROUND: Polydatin (PD), a monocrystalline and polyphenolic drug isolated from a traditional Chinese herb (Polygonum cuspidatum), is protective against mitochondrial dysfunction and has been approved for clinical trials in the treatment of shock. However, whether the administration of PD has a therapeutic effect on multiple-organ dysfunction syndrome (MODS) requires investigation. MATERIAL AND METHODS: MODS was induced in Sprague-Dawley rats via hemorrhage and ligation and puncture of cecum-induced sepsis. The rats were divided into three groups as follows: MODS + PD, MODS + normal saline, and a control group (no treatment). Survival time, blood biochemical indexes, and histopathologic changes in various organs were evaluated; serum oxidative stress (advanced oxidative protein products [AOPPs]) and proinflammatory cytokines (tumor necrosis factor-α, interleukin 1ß, and interleukin 6) were assayed using enzyme-linked immunosorbent assay. Apoptosis-related protein expression (B-cell lymphoma-2 [Bcl-2] and Bax) was assayed by immunohistochemical and Western blotting methods, whereas caspase-3 activity was assayed by spectrophotometry. RESULTS: PD improved organ function, prolonged survival time, and reduced MODS incidence and serum levels of AOPPs and proinflammatory cytokines. It also decreased Bax levels and caspase-3 activity and increased Bcl-2 levels in the kidney and liver. CONCLUSIONS: PD may serve as a potential therapeutic for MODS, as it suppresses oxidative stress, inhibits inflammatory response, attenuates apoptosis, and protects against mitochondrial dysfunction.