title: p-Cresol mediates autophagic cell death in renal proximal tubular cells.
abstract: Higher serum level of p-cresol (PC) in chronic kidney disease (CKD) patients has been linked with CKD progression. The toxic effect of PC on diverse cells has been reported by prior studies, except for renal tubular cells. Both autophagy and apoptosis contribute to renal tubular cell death, yet evidence of its response to PC is limited and their crosstalk is still unclear. Autophagy is an important cellular process involved in toxin-induced cell death. Renal tubular cell death in tubular injury is thought to be one of the key events causing the progression of CKD. Thus, we treated rat (NRK-52E) and human (HRPTEC) renal proximal tubular cells (RPTC) with PC and found the cell proliferation was significantly decreased. Cell apoptosis was significantly increased and accompanied with the activation of autophagy as evidenced by increases in LC3-II, beclin 1 and Atg 4. We also found an increase of p62 by c-Jun activation. p62 accumulation could mediate the activation of caspase 8-dependent cell apoptosis. Conversely, knockdown of p62 by siRNA of p62 had the opposite effect by arresting LC3-II accumulation and promoting increasing cell viability. We conclude that PC triggered autophagic RPTC death via JNK-mediated p62 accumulation and then activated caspase 8-dependent cell death pathway. PC can be considered as one of the key events causing progression of CKD, which might affect drug disposition in CKD cases.
authors: Division of Nephrology and Kidney Institute, Department of Medicine, China Medical University Hospital, Taiwan; Graduate Institute of Clinical Medical Science, College of Medicine, China Medical University, Taiwan.
authors: Hsin-Hung
authors: HH
authors: Lin
authors: Division of Nephrology and Kidney Institute, Department of Medicine, China Medical University Hospital, Taiwan; Graduate Institute of Clinical Medical Science, College of Medicine, China Medical University, Taiwan.
authors: Chiu-Ching
authors: CC
authors: Huang
authors: Department of Pathology, China Medical University Hospital, Taiwan.
authors: Tze-Yi
authors: TY
authors: Lin
authors: Graduate Institute of Clinical Medical Science, College of Medicine, China Medical University, Taiwan; Clinical Immunological Center and Division of Pediatrics Nephrology, Children's Hospital of China Medical University, Taiwan. Electronic address: cylin@mail.cmuh.org.tw.
authors: Ching-Yuang
authors: CY
authors: Lin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000032:analysis; D001343:Autophagy / Q000187:drug effects; D000071186:Beclin-1; D053181:Caspase 8 / Q000032:analysis; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003408:Cresols / Q000633:toxicity*; D004847:Epithelial Cells; D005434:Flow Cytometry; D006360:Heat-Shock Proteins / Q000032:analysis; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008856:Microscopy, Fluorescence; D051381:Rats; D051436:Renal Insufficiency, Chronic / Q000378:metabolism / Q000473:pathology; D000071456:Sequestosome-1 Protein
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C512829:Becn1 protein, rat; D003408:Cresols; D006360:Heat-Shock Proteins; D000071456:Sequestosome-1 Protein; C491079:Sqstm1 protein, rat; C032538:4-cresol; D053181:Caspase 8
keywords: Apoptosis; Autophagy; Chronic kidney disease; Renal proximal tubular cell; p-Cresol; p62/SQSTM1