Ketamine Induced Bladder Fibrosis Through MTDH/P38 MAPK/EMT Pathway

Area of Science:

• Urology
• Molecular Biology
• Toxicology

Background:

• Ketamine is an anesthetic with abuse potential, leading to ketamine-induced cystitis (KIC).
• Bladder fibrosis is a severe, late-stage complication of KIC, posing a significant health risk to abusers.
• Understanding the molecular mechanisms underlying ketamine-induced bladder fibrosis is crucial for developing effective treatments.

Purpose of the Study:

• To investigate the molecular mechanisms driving ketamine-induced bladder fibrosis.
• To identify key molecular players and pathways involved in the pathogenesis of KIC-related fibrosis.
• To explore the role of Metadherin (MTDH) in ketamine-induced bladder fibrosis.

Main Methods:

• Female Sprague Dawley rats were administered ketamine (25 or 50 mg/kg/day) or saline for 12 weeks.
• Bladder tissues were analyzed using HE staining, Masson's trichrome staining, and immunohistochemistry.
• In vitro studies used SV-HUC-1 cells treated with ketamine, with subsequent analysis of MTDH, P38 MAPK, and epithelial-mesenchymal transition (EMT) markers via Western blot and RT-PCR. Gene knockdown and overexpression were employed.

Main Results:

• Ketamine administration induced significant bladder fibrosis in rats and increased fibrosis markers in SV-HUC-1 cells in a dose-dependent manner.
• Ketamine treatment upregulated MTDH, P38 MAPK, and EMT markers in SV-HUC-1 cells.
• MTDH knockdown inhibited the P38 MAPK/EMT pathway and suppressed fibrosis, while MTDH overexpression promoted it.

Conclusions:

• Metadherin (MTDH) plays a critical role in ketamine-induced bladder fibrosis.
• MTDH regulates bladder fibrosis by modulating the epithelial-mesenchymal transition (EMT) via the P38 MAPK pathway.
• Targeting the MTDH/P38 MAPK/EMT axis presents a potential therapeutic strategy for managing ketamine-induced bladder fibrosis.