PMID- 26517816
OWN - NLM
STAT- MEDLINE
DCOM- 20160902
LR  - 20220410
IS  - 1421-9670 (Electronic)
IS  - 0250-8095 (Linking)
VI  - 42
IP  - 4
DP  - 2015
TI  - Lipopolysaccharide Induces Chronic Kidney Injury and Fibrosis through Activation 
      of mTOR Signaling in Macrophages.
PG  - 305-17
LID - 10.1159/000441506 [doi]
AB  - 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 microg/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-1beta and MCP-1 in cultured RAW264.7 cells, which was significantly suppressed by 
      rapamycin. CONCLUSION: 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.
CI  - (c) 2015 S. Karger AG, Basel.
FAU - Chen, Huihui
AU  - Chen H
AD  - Department of Ophthalmology, The Second Xiangya Hospital, Central South 
      University, Changsha, Hunan, PR China.
FAU - Zhu, Jiefu
AU  - Zhu J
FAU - Liu, Yu
AU  - Liu Y
FAU - Dong, Zheng
AU  - Dong Z
FAU - Liu, Hong
AU  - Liu H
FAU - Liu, Yinghong
AU  - Liu Y
FAU - Zhou, Xiang
AU  - Zhou X
FAU - Liu, Fuyou
AU  - Liu F
FAU - Chen, Guochun
AU  - Chen G
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20151031
PL  - Switzerland
TA  - Am J Nephrol
JT  - American journal of nephrology
JID - 8109361
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (IL1B protein, mouse)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (RNA, Messenger)
RN  - 9007-34-5 (Collagen)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Cell Line
MH  - Chemokine CCL2/*drug effects/genetics/metabolism
MH  - Collagen/drug effects/metabolism
MH  - Endotoxemia/complications/*metabolism/pathology
MH  - Fibrosis
MH  - Fluorescent Antibody Technique
MH  - Immunohistochemistry
MH  - Immunosuppressive Agents/pharmacology
MH  - Injections, Intraperitoneal
MH  - Interleukin-1beta/*drug effects/genetics/metabolism
MH  - Kidney/*drug effects/metabolism/pathology
MH  - Kidney Tubules/drug effects/pathology
MH  - Lipopolysaccharides/*toxicity
MH  - Macrophages/*drug effects/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - RNA, Messenger/*drug effects/metabolism
MH  - Real-Time Polymerase Chain Reaction
MH  - Renal Insufficiency, Chronic/etiology/*metabolism/pathology
MH  - Signal Transduction/drug effects
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases/*drug effects/metabolism
EDAT- 2015/10/31 06:00
MHDA- 2016/09/03 06:00
CRDT- 2015/10/31 06:00
PHST- 2015/09/08 00:00 [received]
PHST- 2015/10/01 00:00 [accepted]
PHST- 2015/10/31 06:00 [entrez]
PHST- 2015/10/31 06:00 [pubmed]
PHST- 2016/09/03 06:00 [medline]
AID - 000441506 [pii]
AID - 10.1159/000441506 [doi]
PST - ppublish
SO  - Am J Nephrol. 2015;42(4):305-17. doi: 10.1159/000441506. Epub 2015 Oct 31.