ABSTRACT
In septic acute kidney injury (SAKI), the positive feedback between damaged mitochondria and accumulation of reactive oxygen species results in cell and tissue damage through multiple mechanisms. Removing the damaged mitochondria or neutralizing the reactive oxygen species has been considered beneficial to alleviating cell damage. The antioxidant Procyanidin B2 has been reported to inhibits reactive oxygen species and thereby reduces cell injury. However, it is unclear whether this effect is associated with clearance of damaged mitochondria. Here, we evaluated the efficacy of procyanidin B2 on SAKI, and focused on its effects on mitochondrial dynamics and removing damaged mitochondria via mitophagy. The results showed that the renal function, renal tubular cell vacuolization and oxidative stress were decreased in SAKI mice treated with procyanidin B2, moreover, skewed mitochondrial fusion/fission, mitochondrial mediated apoptosis and impaired mitophagy were improved in SAKI mice treated with procyanidin B2. In mechanism, the improvement of procyanidin B2 on mitochondrial dynamics were associated with increased nuclear translocation of the transcription factor, Nrf2. In summary, our findings highlighted that the protective efficacy of procyanidin B2 in reducing cellular damage in SAKI, and mechanisms improving mitochondrial dynamics and quality control at least in part by promoting Nrf2 translocation into the nucleus.
Subject(s)
Acute Kidney Injury/prevention & control , Antioxidants/pharmacology , Biflavonoids/pharmacology , Catechin/pharmacology , Kidney/drug effects , Mitochondria/drug effects , Mitochondrial Dynamics/drug effects , NF-E2-Related Factor 2/metabolism , Proanthocyanidins/pharmacology , Sepsis/drug therapy , Active Transport, Cell Nucleus , Acute Kidney Injury/etiology , Acute Kidney Injury/metabolism , Acute Kidney Injury/pathology , Animals , Apoptosis/drug effects , Disease Models, Animal , Kidney/metabolism , Kidney/ultrastructure , Male , Mice, Inbred C57BL , Mitochondria/metabolism , Mitochondria/ultrastructure , Mitophagy/drug effects , Oxidative Stress/drug effects , Sepsis/complications , Sepsis/metabolismABSTRACT
The transcription factor EB (TFEB) regulates the expression of target genes bearing the Coordinated Lysosomal Expression and Regulation (CLEAR) motif, thereby modulating autophagy and lysosomal biogenesis. Furthermore, TFEB can bind to the promoter of autophagy-associated genes and induce the formation of autophagosomes, autophagosome-lysosome fusion, and lysosomal cargo degradation. An increasing number of studies have shown that TFEB stimulates the intracellular clearance of pathogenic factors by enhancing autophagy and lysosomal function in multiple kidney diseases, such as cystinosis, acute kidney injury, and diabetic nephropathy. Taken together, this highlights the importance of developing novel therapeutic strategies against kidney diseases based on TFEB regulation. In this review, we present an overview of the current data on TFEB and its implication in kidney disease.
ABSTRACT
Mitochondria are energy producers that play a vital role in cell survival. Mitochondrial dysfunction is involved in many diseases, including metabolic syndrome, neurodegenerative disorders, cardiomyopathies, cancer, obesity, and diabetic kidney disease, and challenges still remain in terms of treatments for these diseases. Mitochondrial quality control (MQC), which is defined as the maintenance of the quantity, morphology, and function of mitochondria, plays a pivotal role in maintaining cellular metabolic homeostasis and cell survival. Recently, growing evidence suggests that the transcription factor EB (TFEB) plays a pivotal role in MQC. Here, we systemically investigate the potential role and mechanisms of TFEB in MQC, which include the activation of mitophagy, regulation of mitochondrial biogenesis, reactive oxygen species (ROS) clearance, and the balance of mitochondria fission-fusion cycle. Importantly, we further discuss the therapeutic measures and effects aimed at TFEB on mitochondrial dysfunction-related diseases. Taken together, targeting TFEB to regulate MQC may represent an appealing therapeutic strategy for mitochondrial dysfunction related-diseases.
Subject(s)
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , Energy Metabolism , Mitochondria/metabolism , Mitophagy , Organelle Biogenesis , Oxidative Stress , Animals , Humans , Mitochondria/pathology , Oxidation-Reduction , Reactive Oxygen Species/metabolism , Signal TransductionABSTRACT
AIMS: The renal tubule cells require a large number of mitochondria to supply ATP due to their high-energy demand during reabsorption and secretion against chemical gradients and result in mitochondria susceptible to disorder and injury during stress conditions. Injured mitochondria are eventually degraded by mitophagy, and disturbances in mitophagy are associated with the pathogenesis of acute kidney injury (AKI) such as diabetic nephropathy and glomerulosclerosis. However, whether a disturbance in mitophagy has occurred and the role it plays in (SAKI) is still unclear. Therefore, the aim of this study was to investigate the key features of mitophagy and mitochondrial dynamics in sepsis-induced acute kidney injury (SAKI). MAIN METHODS: In this study, a murine septic AKI model induced by cecal ligation and puncture (CLP) was built; mitophagy and mitochondrial dynamics were measured in mice kidney in different time point. KEY FINDINGS: The results showed that mitochondrial dynamics were characterized by fission/fusion aberrant, however more inclined to fission, and mitochondrial associated apoptosis was elevated over-time during SAKI. Furthermore, mitophagy was impaired in the later phase of SAKI, although elevated in early stage of SAKI. The results indicate that the underlying mechanisms of impaired mitophagy may associate with the cleavage of Parkin via caspases activated by NLRP3, at least partly. SIGNIFICANCE: It is conceivable that this selective autophagic process and quality control machinery was impaired, leading to the accumulation of damaged mitochondria, oxidative stress, and cell death. Therefore, a targeted approach, by enhancing mitophagy during SAKI, may be a promising therapeutic strategy.
Subject(s)
Acute Kidney Injury/etiology , Acute Kidney Injury/physiopathology , Mitochondrial Dynamics/physiology , Mitophagy/physiology , Sepsis/complications , Sepsis/physiopathology , Acute Kidney Injury/metabolism , Animals , Apoptosis/physiology , Apoptosis Regulatory Proteins/metabolism , Male , Mice , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Sepsis/metabolism , Ubiquitin-Protein Ligases/metabolismABSTRACT
Genistein is an isoflavone derived from soy-rich products, which is known to exhibit several beneficial biological effects, such as anti-tumor activity, improvement of glucose metabolism, and reduction of the frequency of peri-menopausal hot flashes, and thus has potential for clinical application. Certain limitations and side effects, such as low bioavailability, biological estrogenic activity, and detrimental effects on thyroid function, have restricted its clinical applications to some extent. Recently, it has been reported that fermentation, use of micromicelles, and modification of its chemical structure can enhance the bioavailability of genistein. Moreover, the modification of its molecular structure may also eliminate its biological estrogenic activity and adverse effects on thyroid function. In this review, we summarize the clinical application prospects and limitations of genistein, as well as the plausible solutions to overcome its low bioavailability, phytoestrogenic activity, and adverse effects on thyroid function.
