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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Vydáno v:	Cell death & disease Ročník 9; číslo 3; s. 351 - 14
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 02.03.2018 Springer Nature B.V
Témata:	13/21 13/51 13/89 14 14/19 38 38/77 64/60 82/80 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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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-4889 2041-4889
DOI:	10.1038/s41419-018-0378-3