PINK1-parkin pathway of mitophagy protects against contrast-induced acute kidney injury via decreasing mitochondrial ROS and NLRP3 inflammasome activation

Redox Biology, Год журнала: 2019, Номер 26, С. 101254 - 101254

Опубликована: Июнь 11, 2019

Contrast-induced acute kidney injury (CI-AKI) occurs in more than 30% of patients after intravenous iodinated contrast media and causes serious complications, including renal failure mortality. Recent research has demonstrated that routine antioxidant alkaline therapy failed to show benefits CI-AKI with high risk for complications. Mitophagy is a mechanism selective autophagy, which controls mitochondrial quality reactive oxygen species (ROS) through degradation damaged mitochondria. The role mitophagy its regulation apoptosis are poorly understood. In this study, we was induced tubular epithelial cells (RTECs) during CI-AKI, both vivo vitro. Meanwhile, media-induced abolished when silencing PINK1 or PARK2 (Parkin), indicating dominant the PINK1-Parkin pathway mitophagy. Moreover, damage, ROS, RTEC apoptosis, under exposure were severe PINK1- PARK2-deficient mice wild-type groups. Functionally, PINK1-Parkin-mediated prevented tissue damage reducing ROS subsequent NLRP3 inflammasome activation. These results played protective by

Язык: Английский

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Inhibiting NLRP3 inflammasome attenuates apoptosis in contrast-induced acute kidney injury through the upregulation of HIF1A and BNIP3-mediated mitophagy

Autophagy, Год журнала: 2020, Номер 17(10), С. 2975 - 2990

Опубликована: Дек. 19, 2020

The pathogenetic mechanism of contrast-induced acute kidney injury (CI-AKI), which is the third most common cause hospital-acquired AKI, has not been elucidated. Previously, we demonstrated that renal and cell apoptosis were attenuated in nlrp3 knockout CI-AKI mice. Here, investigated underlying NLRP3 inhibition-mediated attenuation CI-AKI. RNA sequencing analysis cortex revealed or casp1 mice exhibited upregulated cellular response to hypoxia, mitochondrial oxidation, autophagy when compared with wild-type (WT) mice, indicated inflammasome inhibition resulted upregulation hypoxia signaling pathway mitophagy. iohexol-treated HK-2 cells MCC950 pretreatment levels HIF1A, BECN1, BNIP3, LC3B-II, as well enhanced colocalization LC3B BNIP3 mitochondria, mitochondria lysosomes. Additionally, roxadustat, a HIF prolyl-hydroxylase inhibitor, protected tubular epithelial against iohexol-induced through stabilization HIF1A activation downstream BNIP3-mediated mitophagy vivo vitro. Moreover, deficiency markedly decreased mitophagy, also significantly exacerbated injury. This suggested protective function study elucidated novel this potential applications roxadustat clinical treatment.Abbreviations: BNIP3: BCL2/adenovirus E1B interacting protein 3; Ctrl: control; DAPI: 4',6-diamidino-2-phenylindole dihydrochloride; EGLN2/PHD1: egl-9 family hypoxia-inducible factor 2; HIF1A: inducible 1, alpha subunit; H-E: hematoxylin eosin; IL18: interleukin 18; IL1B: 1 beta; LAMP1: lysosomal-associated membrane 1; MAP1LC3B/LC3B: microtubule-associated light chain 3 mRNA: messenger RNA; NFKB/NF-κB: nuclear kappa polypeptide gene enhancer B cells; NLRP3: NLR family, pyrin domain containing NS: normal saline; PRKN/Parkin: parkin RBR E3 ubiquitin ligase; PINK1: PTEN induced putative kinase RNA: ribonucleic acid; SEM: standard error mean; siRNA: small interfering TEM: transmission electron microscopy; TUBA/α-tubulin: tubulin, alpha; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; VDAC: voltage-dependent anion channel; WT: wild-type.

Язык: Английский

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The mitophagy pathway and its implications in human diseases

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Авг. 16, 2023

Abstract Mitochondria are dynamic organelles with multiple functions. They participate in necrotic cell death and programmed apoptotic, crucial for metabolism survival. Mitophagy serves as a cytoprotective mechanism to remove superfluous or dysfunctional mitochondria maintain mitochondrial fine-tuning numbers balance intracellular homeostasis. Growing evidences show that mitophagy, an acute tissue stress response, plays important role maintaining the health of network. Since timely removal abnormal is essential survival, cells have evolved variety mitophagy pathways ensure can be activated time under various environments. A better understanding diseases treatment therapeutic target design. In this review, we summarize molecular mechanisms mitophagy-mediated elimination, how maintains homeostasis at system levels organ, what alterations related development diseases, including neurological, cardiovascular, pulmonary, hepatic, renal disease, etc., recent advances. Finally, potential clinical applications outline conditions regulators enter trials. Research advances signaling transduction will developing new strategies precision medicine.

Язык: Английский

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Kidney physiology and susceptibility to acute kidney injury: implications for renoprotection

Nature Reviews Nephrology, Год журнала: 2021, Номер 17(5), С. 335 - 349

Опубликована: Фев. 5, 2021

Язык: Английский

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A Lipid Droplet-Specific NIR Fluorescent Probe with a Large Stokes Shift for In Vivo Visualization of Polarity in Contrast-Induced Acute Kidney Injury

Analytical Chemistry, Год журнала: 2023, Номер 95(31), С. 11785 - 11792

Опубликована: Июль 7, 2023

The research on lipid droplets (LDs) has attracted great attention in the field of biomedical science recent years. LD malfunction is found to be associated with development acute kidney injury (AKI). To monitor this biological process and explain related pathological behavior, excellent fluorescent probes a polarity-sensitive character would provide desirable strategy. Herein, we designed new polarity-susceptible probe named LD-B targetability, which exhibits very weak fluorescence highly polar solvents based twisted intramolecular charge transfer effect but enhanced low environments, enabling us visualize polarity alteration. also possesses merits intense near-infrared (NIR) emission, good photostability, large Stokes shift, toxicity, faster metabolic rate, wash-free ability; thereby, it contribute efficient visualization application. Using via confocal laser scanning imaging small-animal system vivo, first manifested prominent rise contrast-induced AKI (CI-AKI), not only at cellular level animals vivo. Furthermore, vivo studies suggest that could accumulate kidney. In addition, normal cell lines (including cells) exhibiting greater LDs than cancer cells have been demonstrated systemically. Altogether, our work presents an effective approach for medical diagnosis CI-AKI identification potential therapeutic markers.

Язык: Английский

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Klotho alleviates contrast-induced acute kidney injury by suppressing oxidative stress, inflammation, and NF-KappaB/NLRP3-mediated pyroptosis

International Immunopharmacology, Год журнала: 2023, Номер 118, С. 110105 - 110105

Опубликована: Апрель 3, 2023

Язык: Английский

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A Renal‐Clearable Duplex Optical Reporter for Real‐Time Imaging of Contrast‐Induced Acute Kidney Injury

Angewandte Chemie International Edition, Год журнала: 2019, Номер 58(49), С. 17796 - 17804

Опубликована: Окт. 11, 2019

Despite its high morbidity and mortality, contrast-induced acute kidney injury (CIAKI) remains a diagnostic dilemma because it relies on in vitro detection of insensitive late-stage blood urinary biomarkers. We report the synthesis an activatable duplex reporter (ADR) for real-time vivo imaging CIAKI. ADR is equipped with chemiluminescence near-infrared fluorescence (NIRF) signaling channels that can be activated by oxidative stress (superoxide anion, O2.- ) lysosomal damage (N-acetyl-β-d-glucosaminidase, NAG), respectively. By virtue renal clearance efficiency (80 % injected doses after 24 h injection), detects sequential upregulation NAG kidneys living mice prior to significant decrease glomerular filtration rate (GFR) tissue course outperforms typical clinical assays CIAKI at least 8 up 16 (chemiluminescence) earlier.

Язык: Английский

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Renal hypoxia in kidney disease: Cause or consequence?

Acta Physiologica, Год журнала: 2017, Номер 222(4)

Опубликована: Ноя. 21, 2017

Tissue hypoxia has been proposed as an important factor in the pathophysiology of both chronic kidney disease (CKD) and acute injury (AKI), initiating propagating a vicious cycle tubular injury, vascular rarefaction, fibrosis thus exacerbation hypoxia. Here, we critically evaluate this proposition by systematically reviewing literature relevant to following six questions: (i) Is always associated with tissue hypoxia? (ii) Does drive signalling cascades that lead damage dysfunction? (iii) per se disease? (iv) precede pathology? (v) colocalize (vi) prevention prevent We conclude is common feature AKI CKD. Furthermore, at least under vitro conditions, renal drives dysfunction. itself can pathology, independent other known risk factors for disease. There also some evidence precedes forms However, have made relatively little progress determining spatial relationships between pathological processes (i.e. colocalization) or whether therapies targeted reduce delay progression Thus, hypothesis "common pathway" CKD still remains be adequately tested.

Язык: Английский

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Mitophagy in Acute Kidney Injury and Kidney Repair

Cells, Год журнала: 2020, Номер 9(2), С. 338 - 338

Опубликована: Фев. 1, 2020

Acute kidney injury (AKI) is a major disease characterized by rapid decline of renal function. Besides its acute consequence high mortality, AKI has recently been recognized as an independent risk factor for chronic (CKD). Maladaptive or incomplete repair tubules after severe episodic leads to fibrosis and, eventually, CKD. Recent studies highlight key role mitochondrial pathology in development and abnormal AKI. As such, timely elimination damaged mitochondria tubular cells represents important quality control mechanism cell homeostasis survival during repair. Mitophagy selective form autophagy that selectively removes redundant mitochondria. Here, we summarize our recent understanding on the molecular mechanisms mitophagy, discuss mitophagy AKI, present future research directions therapeutic potential.

Язык: Английский

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Immunopathophysiology of trauma-related acute kidney injury

Nature Reviews Nephrology, Год журнала: 2020, Номер 17(2), С. 91 - 111

Опубликована: Сен. 21, 2020

Язык: Английский

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