title: Rapamycin attenuates aldosterone-induced tubulointerstitial inflammation and fibrosis.
abstract: OBJECTIVE
  Aldosterone (Aldo), a mediator of kidney fibrosis, is implicated in the pathogenesis of chronic kidney diseases (CKD). The aim of this study was to evaluate the regulatory role of rapamycin (Rap) in Aldo-induced tubulointerstitial inflammation and fibrosis.
  
  
  METHODS
  Uninephrectomized, Sprague-Dawley rats were given 1% NaCl (salt) to drink and were randomized to receive treatment for 28 days as follows: vehicle infusion (control), 0.75 μg/h Aldo subcutaneous infusion, or Aldo infusion plus 1 mg/kg/day of Rap by intraperitoneal injection. The effect of Rap on Aldo-induced fibrosis and renal inflammation was investigated using Masson's technique, immunohistochemistry, and western blotting. The effects of Rap on the Aldo-induced epithelial-mesenchymal transition (EMT) process and on TNF-α mRNA expression and secretion in cultured HK-2 cells were investigated by immunofluorescent staining, western blot, qRT-PCR and ELISA.
  
  
  RESULTS
  An in vivo study indicated that signaling by the mammalian target of Rap (mTOR) was activated in rats in the Aldo group compared to controls, as indicated by up-regulated expression of p-mTOR and p-S6K. In addition, the inflammatory response increased, as evidenced by increases in inflammatory markers (MCP-1, ICAM-1, F4/80), and the accumulation of extracellular matrix (ECM), as indicated by increased collagen I and fibronectin expression and pro-fibrogenic gene (PAI-1 and TGF-β1) expression. These changes were attenuated by Rap treatment. An in vitro study showed that Rap significantly suppressed the Aldo-induced EMT process and TNF-α mRNA expression and secretion in cultured HK-2 cells.
  
  
  CONCLUSIONS
  Rap can ameliorate tubulointerstitial inflammation and fibrosis by blocking mTOR signaling. Tubular cells may be a major cell type involved in this physiologic process.
authors.affiliation: Division of Nephrology, Huashan Hospital and Institute of Nephrology, Fudan University, Shanghai, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Ding
authors.forename: Minmin
authors.initials: M
authors.lastname: Zhang
authors.forename: Hongmei
authors.initials: H
authors.lastname: Li
authors.forename: Yong
authors.initials: Y
authors.lastname: Gu
mesh_terms: D000450:Aldosterone / Q000633:toxicity; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005109:Extracellular Matrix / Q000378:metabolism; D005355:Fibrosis / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D008297:Male; D009395:Nephritis, Interstitial / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D017395:Plasminogen Activator Inhibitor 1; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D000450:Aldosterone; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus