Aspirin-triggered resolvin D1 down-regulates inflammatory responses and protects against endotoxin-induced acute kidney injury.
The presence of endotoxin in blood can lead to acute kidney injury (AKI) and septic shock. Resolvins, the endogenous lipid mediators derived from docosahexaenoic acid, have been reported to exhibit potent anti-inflammatory action. Using a mouse model of lipopolysaccharide (LPS)-induced AKI, we investigated the effects of aspirin-triggered resolvin D1 (AT-RvD1) on inflammatory kidney injury. Administration of AT-RvD1 1h after LPS challenge protected the mice from kidney injury as indicated by the measurements of blood urea nitrogen, serum creatinine, and morphological alterations associated with tubular damage. The protective effects were evidenced by decreased neutrophil infiltration in the kidney indicating reduction in inflammation. AT-RvD1 treatment restored kidney cell junction protein claudin-4 expression, which was otherwise reduced after LPS challenge. AT-RvD1 treatment inhibited endotoxin-induced NF-κB activation and suppressed LPS-induced ICAM-1 and VCAM-1 expression in the kidney. Moreover, AT-RvD1 treatment markedly decreased LPS-induced IL-6 level in the kidney and blocked IL-6-mediated signaling including STAT3 and ERK phosphorylation. Our findings demonstrate that AT-RvD1 is a potent anti-inflammatory mediator in LPS-induced kidney injury, and AT-RvD1 has therapeutic potential against AKI during endotoxemia.
Center for Research on Environmental Disease, University of Kentucky, Lexington, KY 40536, USA.
Jiao
J
Chen
Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA.
Sreerama
S
Shetty
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China.
Ping
P
Zhang
Center for Research on Environmental Disease, University of Kentucky, Lexington, KY 40536, USA.
Rong
R
Gao
Center for Research on Environmental Disease, University of Kentucky, Lexington, KY 40536, USA.
Yuxin
Y
Hu
Graduate Center for Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.
Shuxia
S
Wang
Division of Cardiovascular Medicine, University of Kentucky, Lexington, KY 40536, USA.
Zhenyu
Z
Li
Center for Research on Environmental Disease, University of Kentucky, Lexington, KY 40536, USA; Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536, USA. Electronic address: jian.fu@uky.edu.
Jian
J
Fu
D058186:Acute Kidney Injury / Q000097:blood / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D001806:Blood Urea Nitrogen; D062506:Claudin-4 / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D019610:Cytoprotection; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D004731:Endotoxins; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D062506:Claudin-4; C568158:Cldn4 protein, mouse; D004731:Endotoxins; C090509:Icam1 protein, mouse; D018836:Inflammation Mediators; D015850:Interleukin-6; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D019010:Vascular Cell Adhesion Molecule-1; C518399:resolvin D1; D018799:Intercellular Adhesion Molecule-1; D004281:Docosahexaenoic Acids; C044101:endotoxin, Escherichia coli; D003404:Creatinine; D048049:Extracellular Signal-Regulated MAP Kinases; D001241:Aspirin
Acute kidney injury; Aspirin-triggered resolvin D1; Endotoxemia; Inflammation; Sepsis