title: Uropathogenic Escherichia coli toxins induce caspase-independent apoptosis in renal proximal tubular cells via ERK signaling.
abstract: BACKGROUND
  Pyelonephritis is a risk factor for renal tubular epithelial cell damage. Recent studies have shown that Escherichia coli and/or its toxins may stimulate apoptotic cell death in renal tubular cells, but the underlying molecular mechanisms remain to be elucidated.
  
  
  METHODS
  Confluent LLC-PK(1) cells were exposed to E. coli toxins from overnight cultures of the uropathogenic O6K13H1 (O6) and the nonpathogenic W3110. The cell death was studied with morphological and biological assay.
  
  
  RESULTS
  E. coli soluble toxins from uropathogenic O6:K13:H1(O6) strain were found to induce apoptosis in a dose- and time-dependent manner in LLC-PK1 cells. The expression of FasR and the phosphorylation of ERK1/2 were significantly upregulated by O6 soluble toxins in a time-dependent manner. Cell death was completely inhibited by two specific ERK1/2 inhibitors, but not by a broad caspase inhibitor, zVAD-fmk, implicating a caspase-independent pathway via ERK. Moreover, we found that lysophosphatidic acid could trigger a survival signal through G-proteins and PI3K.
  
  
  CONCLUSIONS
  We demonstrate that apoptosis induced by uropathogenic E. coli toxins is dependent on ERK1/2. Caspases, although being activated, are not necessary for cell death, and they act after the ERK signaling at which point cells become committed to cell death or can be rescued.
authors.affiliation: Pediatric Nephrology Unit, Pathology and Immunology, Division of Pathology, Karolinska Institutet, Stockholm, Sweden. Ming.Chen@klinvet.ki.se
authors.forename: Ming
authors.initials: M
authors.lastname: Chen
authors.forename: Timo
authors.initials: T
authors.lastname: Jahnukainen
authors.forename: Wenjie
authors.initials: W
authors.lastname: Bao
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Daré
authors.forename: Sandra
authors.initials: S
authors.lastname: Ceccatelli
authors.forename: Gianni
authors.initials: G
authors.lastname: Celsi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001427:Bacterial Toxins / Q000494:pharmacology*; D015153:Blotting, Western; D020169:Caspases / Q000502:physiology*; D002478:Cells, Cultured; D004926:Escherichia coli; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000201:enzymology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D011704:Pyelonephritis / Q000201:enzymology / Q000473:pathology*; D015398:Signal Transduction; D013552:Swine; D015854:Up-Regulation
chemical_list: D001427:Bacterial Toxins; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases