title: The effect of statin on epithelial-mesenchymal transition in peritoneal mesothelial cells.
abstract: BACKGROUND
  Statins have recently been highlighted for their pleiotropic actions distinct from cholesterol-lowering effects. Despite this interest, it is currently unknown whether statin therapy inhibits peritoneal dialysis (PD)-related epithelial-mesenchymal transition (EMT).
  
  
  METHODS
  In vitro, human peritoneal mesothelial cells (HPMCs) were exposed to 5.6 mM glucose (NG) or 100 mM glucose (HG) with or without simvastatin (1 µM). In vivo, PD catheters were inserted into 32 Sprague-Dawley rats, and saline (C, n = 16) or 4.25% peritoneal dialysis fluid (PDF) (PD, n = 16) was infused for 4 weeks. Eight rats from each group were treated with 5 mg/kg/day of simvastatin intraperitoneally. Changes in the protein expression of EMT markers such as E-cadherin, α-SMA, Snail, and fibronectin in HPMCs and the peritoneum were evaluated by Western blot analysis and immunofluorescence or immunohistochemical staining. We also explored whether activation of the mevalonate pathway and its downstream small GTPases were involved in dialysis-related peritoneal EMT and could be inhibited by statin treatment.
  
  
  RESULTS
  Compared to NG cells, E-cadherin expression was significantly decreased, while α-SMA, Snail, and fibronectin expression were significantly increased in HPMCs exposed to HG, and these changes were abrogated by simvastatin (p<0.05). In addition, the cobblestone-like appearance of normal HPMCs was converted into a fibroblast-like morphology after HG treatment, which was reversed by simvastatin. These EMT-like changes were also observed in HPMCs treated with geranyl-geranyl pyrophosphate (5 µM). HG significantly increased the protein expression of RhoA and Rac1 in the membrane fractions, and these increases were ameliorated by simvastatin (p<0.05). In PD rats, E-cadherin in the peritoneum was significantly decreased, whereas α-SMA, Snail, and fibronectin expression were significantly increased (p<0.05) compared to C rats. The thickness of the mesothelial layer in the peritoneum were also significantly greater in PD rats than in C rats (p<0.05). These changes of the peritoneum in PD rats were significantly attenuated by simvastatin.
  
  
  CONCLUSIONS
  This study demonstrated that PD-related EMT was mediated via the mevalonate pathway, and statin treatment inhibited the EMT changes in HG-treated HPMCs and PDF-stimulated PD rats. These findings suggest that statins may be a promising therapeutic strategy for preservation of peritoneal membrane integrity in long-term PD patients.
authors.affiliation: Department of Internal Medicine, College of Medicine, Brain Korea 21 Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University, Seoul, Korea; Department of Internal Medicine, NHIS Medical Center, Ilsan Hospital, Goyang-shi, Gyeonggi-do, Korea.
authors.forename: Tae Ik
authors.initials: TI
authors.lastname: Chang
authors.affiliation: Department of Internal Medicine, College of Medicine, Brain Korea 21 Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University, Seoul, Korea.
authors.forename: Hye-Young
authors.initials: HY
authors.lastname: Kang
authors.affiliation: Department of Surgery, College of Medicine, Brain Korea 21 Project for Medical Sciences, Yonsei University, Seoul, Korea.
authors.forename: Kyung Sik
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, College of Medicine, Brain Korea 21 Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University, Seoul, Korea.
authors.forename: Sun Ha
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, College of Medicine, Brain Korea 21 Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University, Seoul, Korea.
authors.forename: Bo Young
authors.initials: BY
authors.lastname: Nam
authors.affiliation: Department of Internal Medicine, College of Medicine, Brain Korea 21 Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University, Seoul, Korea.
authors.forename: Jisun
authors.initials: J
authors.lastname: Paeng
authors.affiliation: Department of Internal Medicine, College of Medicine, Brain Korea 21 Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University, Seoul, Korea.
authors.forename: Seonghun
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, College of Medicine, Brain Korea 21 Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University, Seoul, Korea.
authors.forename: Jung Tak
authors.initials: JT
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, College of Medicine, Brain Korea 21 Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University, Seoul, Korea.
authors.forename: Tae-Hyun
authors.initials: TH
authors.lastname: Yoo
authors.affiliation: Department of Internal Medicine, College of Medicine, Brain Korea 21 Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University, Seoul, Korea.
authors.forename: Shin-Wook
authors.initials: SW
authors.lastname: Kang
authors.affiliation: Department of Internal Medicine, College of Medicine, Brain Korea 21 Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University, Seoul, Korea.
authors.forename: Seung Hyeok
authors.initials: SH
authors.lastname: Han
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D010537:Peritoneum / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology*; D013729:Terpenes / Q000378:metabolism
chemical_list: D005353:Fibronectins; D000960:Hypolipidemic Agents; D013729:Terpenes; D019821:Simvastatin; D020559:Monomeric GTP-Binding Proteins; D008798:Mevalonic Acid