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, a-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 a-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.
Conclusion: 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.
| Original language | English |
|---|---|
| Article number | e109628 |
| Journal | PloS one |
| Volume | 9 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - 2014 Oct 2 |
Fingerprint
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)
- Agricultural and Biological Sciences(all)
- General
Cite this
}
The effect of statin on epithelial-mesenchymal transition in peritoneal mesothelial cells. / Chang, Tae Ik; Kang, Hye Young; Kim, Kyung Sik; Lee, Sun Ha; Nam, Bo Young; Paeng, Jisun; Kim, Seonghun; Park, Jung Tak; Yoo, Tae Hyun; Kang, Shin Wook; Han, Seung Hyeok.
In: PloS one, Vol. 9, No. 10, e109628, 02.10.2014.Research output: Contribution to journal › Article
TY - JOUR
T1 - The effect of statin on epithelial-mesenchymal transition in peritoneal mesothelial cells
AU - Chang, Tae Ik
AU - Kang, Hye Young
AU - Kim, Kyung Sik
AU - Lee, Sun Ha
AU - Nam, Bo Young
AU - Paeng, Jisun
AU - Kim, Seonghun
AU - Park, Jung Tak
AU - Yoo, Tae Hyun
AU - Kang, Shin Wook
AU - Han, Seung Hyeok
PY - 2014/10/2
Y1 - 2014/10/2
N2 - 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, a-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 a-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.Conclusion: 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.
AB - 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, a-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 a-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.Conclusion: 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.
UR - http://www.scopus.com/inward/record.url?scp=84907486818&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84907486818&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0109628
DO - 10.1371/journal.pone.0109628
M3 - Article
C2 - 25275561
AN - SCOPUS:84907486818
VL - 9
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 10
M1 - e109628
ER -