Comparison of anti-peritoneal fibrotic effects between an mTORC1-specific blocker and a PI3K/mTOR dual-blocker

Area of Science:

• Pharmacology
• Cell Biology
• Nephrology

Background:

• Peritoneal fibrosis is a significant complication of peritoneal dialysis.
• The phosphatidyl-inositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway is implicated in fibrotic processes.
• Targeting this pathway offers a potential therapeutic strategy for peritoneal fibrosis.

Purpose of the Study:

• To compare the efficacy of a specific mammalian target of rapamycin complex 1 (mTORC1) inhibitor, rapamycin (RAPA), against a dual PI3K/mTOR blocker, BEZ235, in mitigating peritoneal fibrosis.
• To elucidate the effects of these inhibitors on key signaling molecules within the mTOR pathway during peritoneal fibrosis.

Main Methods:

• A rat model of peritoneal fibrosis was established using chlorhexidine gluconate.
• Forty Sprague-Dawley rats were divided into five groups: normal, normal saline, model, RAPA treatment, and BEZ235 treatment.
• Animals received daily intraperitoneal injections or oral gavage for three weeks, followed by biochemical and histological analyses.

Main Results:

• Both RAPA and BEZ235 significantly inhibited peritoneal fibrosis, as evidenced by reduced expression of fibrosis markers (FN, Col 1, α-SMA).
• The mTOR pathway was confirmed to be activated in the fibrotic model.
• RAPA inhibited mTOR and p70S6K phosphorylation but not p-Akt, while BEZ235 inhibited phosphorylation of p-Akt, p-mTOR, and p70S6K.

Conclusions:

• Both rapamycin and BEZ235 are effective in inhibiting peritoneal fibrosis.
• BEZ235 demonstrates a broader inhibitory effect on the PI3K/mTOR pathway compared to rapamycin.
• These findings support the therapeutic potential of targeting the mTOR pathway to manage peritoneal fibrosis.