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- Title
Lipopolysaccharide Induces Chronic Kidney Injury and Fibrosis through Activation of mTOR Signaling in Macrophages.
- Authors
Chen, Huihui; Zhu, Jiefu; Liu, Yu; Dong, Zheng; Liu, Hong; Liu, Yinghong; Zhou, Xiang; Liu, Fuyou; Chen, Guochun
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusion: </bold>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.
- Subjects
RNA metabolism; ANIMAL experimentation; CELL lines; CELLULAR signal transduction; CHRONIC kidney failure; COLLAGEN; FLUORESCENT antibody technique; IMMUNOHISTOCHEMISTRY; IMMUNOSUPPRESSIVE agents; INFLAMMATORY mediators; INJECTIONS; INTERLEUKIN-1; KIDNEY tubules; KIDNEYS; MACROPHAGES; MICE; POLYMERASE chain reaction; RNA; WESTERN immunoblotting; RAPAMYCIN; FIBROSIS; ENDOTOXEMIA; LIPOPOLYSACCHARIDES; DISEASE complications; PHARMACODYNAMICS; METABOLISM
- Publication
American Journal of Nephrology, 2015, Vol 42, Issue 4, p305
- ISSN
0250-8095
- Publication type
journal article
- DOI
10.1159/000441506