title: Effects of 2-bromoethanamine on TonEBP expression and its possible role in induction of renal papillary necrosis in mice.
abstract: Chronic analgesic abuse has been shown to induce severe renal injury characterized by renal papillary necrosis (RPN), an injury detectable at late stage. While direct toxicity of the drug may exist, the molecular mechanisms underlying analgesics induction of RPN remain unknown. A major limitation to study the pathogenesis of RPN is the required chronic exposure before detection of injury. Here, we employed 2-bromoethanamine (BEA) to simulate rapid papillary toxicity using inner medullary collecting duct (IMCD3) cells. Although exposure to 10μM BEA had no effect on cellular viability under isotonic conditions, a 50% loss in cell viability was observed in the first 24 h when cells were subjected to sublethal hypertonic stress and nearly complete cell death after 48 h suggesting that BEA exerts cytotoxicity only under hypertonic conditions. Because TonEBP is a transcription factor critical for cell survival during hypertonic conditions, we undertook experiments to examine the effect of BEA on TonEBP expression and activity. Exposure of cells to 10μM BEA resulted in a substantial reduction in TonEBP protein expression after 24 h. In addition, TonEBP was not translocated to the nucleus in BEA-treated IMCD3 cells under acute hypertonic stress for transcription of target genes essential for osmolyte accumulation. Finally, we found a substantial decrease in TonEBP expression in medullary kidney tissues of mice injected with a single ip dose of BEA. Our data suggest that TonEBP is a potential target for BEA leading to the process of papillary necrosis in the settings of hypertonic stress.
authors.affiliation: Division of Renal Diseases and Hypertension, School of Medicine, University of Colorado Denver, Aurora, Colorado 80045, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Andres-Hernando
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Lanaspa
authors.forename: Nanxing
authors.initials: N
authors.lastname: Li
authors.forename: Christina
authors.initials: C
authors.lastname: Cicerchi
authors.forename: Carlos
authors.initials: C
authors.lastname: Roncal-Jimenez
authors.forename: Glenn H
authors.initials: GH
authors.lastname: Cantor
authors.forename: Victor
authors.initials: V
authors.lastname: Sorribas
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Rivard
authors.forename: Tomas
authors.initials: T
authors.lastname: Berl
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005021:Ethylamines / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D006982:Hypertonic Solutions / Q000494:pharmacology; D007679:Kidney Medulla / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007681:Kidney Papillary Necrosis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D007685:Kidney Tubules, Collecting / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D013312:Stress, Physiological / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D005021:Ethylamines; D006982:Hypertonic Solutions; C492200:Nfat5 protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors; C004504:2-bromoethylamine
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