title: Lipopolysaccharide Induces Chronic Kidney Injury and Fibrosis through Activation of mTOR Signaling in Macrophages.
abstract: BACKGROUND
  Septic kidney injury is one of the most common complications in critically ill patients with a high risk of developing chronic kidney disease (CKD). Emerging data indicate that mammalian target of rapamyci (mTOR) signaling plays a major role in septic inflammation by regulating the immune response of macrophage. This study was designed to evaluate the role of mTOR signaling in kidney macrophages during endotoxemia-induced chronic kidney injury and subsequent fibrogenesis.
  
  
  METHODS
  Male C57BL/6 mice were used for all animal studies (n=9 for each group). Lipopolysaccharide (LPS) was injected intraperitoneally (1 mg/kg) every 2 days to induce persistent endotoxemia. Rapamycin (1 mg/kg·day) was administered to a subgroup of mice 1 day prior to LPS treatment and continued to termination of the experiment. In ex-vivo experiment, RAW264.7 cells were cultured and treated with LPS (2 µg/ml) for 48 h while a subgroup of cells were incubated in the presence of rapamycin (50 nmol) for 2 h.
  
  
  RESULTS
  Continuous administration of LPS resulted in progressive macrophage infiltration, tubular injury and collagen deposition in mice kidneys. Rapamycin markedly ameliorated LPS-induced kidney pathological changes. Expression of pS6K was rarely observed in normal kidney macrophages, but significantly increased with time by LPS treatment. In ex-vivo study, LPS induced prominent production of IL-1β and MCP-1 in cultured RAW264.7 cells, which was significantly suppressed by rapamycin.
  
  
  CONCLUSIONS
  Taken together, our findings show that endotoxemia results in activation of mTOR signaling in macrophages, leading to progressive kidney inflammatory injuries and subsequent fibrosis. Our study may reveal a mechanism involved in the development of sepsis-associated CKD and kidney fibrosis.
authors.affiliation: Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, PR China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Chen
authors.forename: Jiefu
authors.initials: J
authors.lastname: Zhu
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Yinghong
authors.initials: Y
authors.lastname: Liu
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhou
authors.forename: Fuyou
authors.initials: F
authors.lastname: Liu
authors.forename: Guochun
authors.initials: G
authors.lastname: Chen
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D018932:Chemokine CCL2 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D003094:Collagen / Q000187:drug effects / Q000378:metabolism; D019446:Endotoxemia / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D053583:Interleukin-1beta / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D051436:Renal Insufficiency, Chronic / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects* / Q000378:metabolism
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C587672:IL1B protein, mouse; D007166:Immunosuppressive Agents; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D003094:Collagen; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus