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Activation of the mTOR dependent signaling pathway underlies ketamine‐induced uropathy
Author(s) -
Lin ChihChieh,
Yang AnHang,
Lin Alex TongLong
Publication year - 2017
Publication title -
neurourology and urodynamics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 90
eISSN - 1520-6777
pISSN - 0733-2467
DOI - 10.1002/nau.23234
Subject(s) - pi3k/akt/mtor pathway , medicine , cd31 , ketamine , sirolimus , mesenchymal stem cell , angiogenesis , signal transduction , pathology , microbiology and biotechnology , biology , anesthesia
AIMS To investigate the pathogenic role of activation of the mammalian target of the rapamycin (mTOR) in the ketamine induced microvascular injury. METHODS Twenty‐three patients with ketamine‐induced cystitis (KC) and 16 control volunteers were recruited. Bladder tissues were obtained from both groups by cystoscopic biopsies. Phospho‐S6 ribosomal protein (p‐S6RP), an end product of the mTOR pathway, was stained in the urinary bladder from both groups. Endothelial cells of the urinary bladder (HBdMECs) were examined to investigate the in vitro activation of the mTOR pathway and the co‐expression of the endothelial marker (cluster of differentiation 31 [CD31]) and the mesenchymal marker (fibroblast‐specific protein 1 [FSP‐1]). RESULTS Expression of p‐S6RP increased significantly after ketamine exposure, especially in the vesical microvessels of KC patients. In HBdMECs treated with 100 µM Ketamine, time‐dependent activation of the mTOR pathway occurred, with significantly increased levels of the phosphorylated forms of mTOR at 30 min and of S6RP and p70S6 kinase (p70S6K) at 6 h. The increased level of p‐S6RP returned to baseline within 2 days after ketamine exposure. The co‐expression of CD31 and FSP‐1 implied that EndMT was present in HBdMECs at 7 days after ketamine treatment, while TGF‐β1 facilitated significant up‐regulation of FSP‐1 at 1 day after treatment. Furthermore, when the mTOR inhibitor rapamycin was administered with ketamine to the HBdMECs, the expression of FSP‐1 decreased significantly. CONCLUSIONS Ketamine induces activation of the mTOR pathway and subsequent mesenchymal phenotypic expression (FSP1) in HBdMECs.