Hydroxychloroquine attenuates renal ischemia/reperfusion injury by inhibiting cathepsin mediated NLRP3 inflammasome activation

Inflammation is a major contributor to the pathogenesis of ischemic acute kidney injury (AKI), which complicates the post-operative outcomes of large numbers of hospitalized surgical patients. Hydroxychloroquine (HCQ), a well-known anti-malarial drug, is commonly used in clinical practice for its an...

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Veröffentlicht in:Cell death & disease Jg. 9; H. 3; S. 351 - 14
Hauptverfasser: Tang, Tao-Tao, Lv, Lin-Li, Pan, Ming-Ming, Wen, Yi, Wang, Bin, Li, Zuo-Lin, Wu, Min, Wang, Feng-Mei, Crowley, Steve D, Liu, Bi-Cheng
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 02.03.2018
Springer Nature B.V
Schlagworte:
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Acute Kidney Injury - drug therapy
Animals
Anti-Inflammatory Agents - metabolism
Anti-Inflammatory Agents - therapeutic use
Antibodies
Biochemistry
Biomedical and Life Sciences
Cathepsin B - metabolism
Cathepsin L
Cathepsin L - metabolism
Cell activation
Cell Biology
Cell Culture
Cell Line
Cell Survival - drug effects
Creatinine
Creatinine - blood
Cytoplasm
Disease Models, Animal
Hepatitis A Virus Cellular Receptor 1 - blood
Humans
Hydroxychloroquine
Hydroxychloroquine - metabolism
Hydroxychloroquine - therapeutic use
Hypoxia
Immunology
Inflammasomes
Inflammasomes - metabolism
Inflammation
Ischemia
Kidneys
Life Sciences
Lysosomes
Macrophages
Macrophages - drug effects
Male
Mice
Mice, Inbred C57BL
Neutrophil Infiltration - drug effects
NF-kappa B - metabolism
NF-κB protein
NLR Family, Pyrin Domain-Containing 3 Protein - metabolism
Renal function
Reperfusion
Reperfusion Injury - drug therapy
Rodents
Surgery
ISSN:2041-4889, 2041-4889
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Zusammenfassung:Inflammation is a major contributor to the pathogenesis of ischemic acute kidney injury (AKI), which complicates the post-operative outcomes of large numbers of hospitalized surgical patients. Hydroxychloroquine (HCQ), a well-known anti-malarial drug, is commonly used in clinical practice for its anti-inflammatory actions. However, little is known about its role in renal ischemia/reperfusion (I/R) injury. In the current study, mice were subjected to I/R injury and HCQ was administered for seven days by gavage prior to surgery. In parallel, HK-2 human renal proximal tubule cells were prophylactically treated with HCQ and then were exposed to hypoxia/reoxygenation (H/R). The results showed that HCQ significantly attenuated renal dysfunction evidenced by blunted decreases in serum creatinine and kidney injury molecular-1 expression and the improvement of HK-2 cell viability. Additionally, HCQ markedly reduced macrophage and neutrophil infiltration, pro-inflammatory cytokine production, and NLRP3 inflammasome activation. Mechanistic studies showed that HCQ could inhibit the priming of the NLRP3 inflammasome by down-regulating I/R or H/R-induced NF-κB signaling. Moreover, HCQ reduced cathepsin (CTS) B, CTSD and CTSL activity, and their redistribution from lysosomes to cytoplasm. CTSB and CTSL (not CTSD) were implicated in I/R triggered NLRP3 inflammasome activation. Notably, we found that HCQ attenuated renal injury through downregulation of CTSB and CTSL-mediated NLRP3 inflammasome activation. This study provides new insights into the anti-inflammatory effect of HCQ in the treatment of AKI.
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SourceType-Scholarly Journals-1
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ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-018-0378-3