title: Heat shock protein 72 enhances autophagy as a protective mechanism in lipopolysaccharide-induced peritonitis in rats.
abstract: Peritoneal dialysis-related peritonitis causes the denudation of mesothelial cells and, ultimately, membrane integrity alterations and peritoneal dysfunction. Because heat shock protein 72 (HSP72) confers protection against apoptosis and because autophagy mediates survival in response to cellular stresses, we examined whether autophagy contributes to HSP72-mediated cytoprotection in lipopolysaccharide (LPS)-induced peritonitis. Exposure of cultured peritoneal mesothelial cells to LPS resulted first in autophagy and later, apoptosis. Inhibition of autophagy by 3-methyladenine or Beclin-1 small-interfering RNA sensitized cells to apoptosis and abolished the antiapoptotic effect of HSP72, suggesting that autophagy activation acts as a prosurvival mechanism. Overexpression of HSP72 augmented autophagy through c-Jun N-terminal kinase (JNK) phosphorylation and Beclin-1 up-regulation. Suppression of JNK activity reversed HSP72-mediated Beclin-1 up-regulation and autophagy, indicating that HSP72-mediated autophagy is JNK dependent. In a rat model of LPS-associated peritonitis, autophagy occurred before apoptosis in peritoneum. Up-regulation of HSP72 by geranylgeranylacetone increased autophagy, inhibited apoptosis, and attenuated peritoneal injury, and these effects were blunted by down-regulation of HSP72 with quercetin. Additionally, blocking autophagy by chloroquine promoted apoptosis and aggravated LPS-associated peritoneal dysfunction. Thus, HSP72 protects peritoneum from LPS-induced mesothelial cells injury, at least in part by enhancing JNK activation-dependent autophagy and inhibiting apoptosis. These findings imply that HSP72 induction might be a potential therapy for peritonitis.
authors: Department of Nephrology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors: Shu
authors: S
authors: Li
authors: Yi
authors: Y
authors: Zhou
authors: Jinjin
authors: J
authors: Fan
authors: Shirong
authors: S
authors: Cao
authors: Tao
authors: T
authors: Cao
authors: Fengxian
authors: F
authors: Huang
authors: Shougang
authors: S
authors: Zhuang
authors: Yihan
authors: Y
authors: Wang
authors: Xueqing
authors: X
authors: Yu
authors: Haiping
authors: H
authors: Mao
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology; D004224:Diterpenes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000378:metabolism; D050884:HSP72 Heat-Shock Proteins / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity*; D049408:Luminescent Agents / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D010529:Peritoneal Cavity / Q000166:cytology; D010538:Peritonitis / Q000139:chemically induced* / Q000517:prevention & control; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C512829:Becn1 protein, rat; D004224:Diterpenes; D050884:HSP72 Heat-Shock Proteins; D008070:Lipopolysaccharides; D049408:Luminescent Agents; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; C025946:3-methyladenine; D002738:Chloroquine; D000225:Adenine; C031049:geranylgeranylacetone