The Effect of Statin on Epithelial-Mesenchymal Transition in Peritoneal Mesothelial Cells

Abstract

BackgroundStatins 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.ResultsCompared 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.ConclusionThis 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.

Lipophilic statins antagonistically alter the major epithelial‐to‐mesenchymal transition signaling pathways in breast cancer stem–like cells via inhibition of the mevalonate pathway

“…The inhibitory effect of statins on peritoneal dialysis‐related epithelial‐mesenchymal transition in rats has been reported. It revealed that statins could reverse the EMT signature, such as low expression of E‐cadherin and high expression of a‐SMA, by the mevalonate pathway . It was also reported that simvastatin inhibits the EMT in TGF‐β1‐treated DU145 prostate cancer cells reducing N ‐cadherin and VIM expressions.…”

“…It revealed that statins could reverse the EMT signature, such as low expression of E-cadherin and high expression of a-SMA, by the mevalonate pathway. 27 It was also reported that simvastatin inhibits the EMT in TGF-β1-treated DU145 prostate cancer cells reducing Ncadherin and VIM expressions. Moreover, it causes an increase in the E-cadherin expression.…”

Neoadjuvant chemotherapy with gemcitabine‑based regimens improves the prognosis of node positive resectable pancreatic head cancer

“…It will be necessary to select agents with EMT inhibitory effect for the primary lesion during preoperative treatment. It is well known that low-dose paclitaxel (41)(42)(43)(44), metformin (45)(46)(47), angiotensin receptor blocker (48,49), statins (50,51), and histone deacetylase inhibitors (52,53) have all been indicated as agents that can inhibit the EMT of tumor cells or activation of stromal cells. Many papers have focused on the inhibition of tumor EMT and CAFs activation with paclitaxel (44,54,55).…”

Cigarette smoke attenuates phagocytic ability of macrophages through down-regulating Milk fat globule-EGF factor 8 (MFG-E8) expressions

“…It was reported that MFG-E8 was implicated in regulating phagocytosis through its interaction with Crk-DOCK180-Rac1 pathway 19 . Rac1 aggregates at the cell membrane which promotes formation of protrusion, thus plays an essential role in phagocytosis 24 . In the present study, 10% CSE stimulation suppressed Rac1 membrane localization in RAW264.7 cells.…”