title: The nephrotoxic Ifosfamide-metabolite chloroacetaldehyde interferes with renal extracellular matrix homeostasis.
abstract: OBJECTIVE
  Chronic renal proximal tubule dysfunction after therapy with the antineoplastic agent ifosfamide (IFO) is often attributed to the metabolite chloroacetaldehyde (CAA). Chronic IFO-nephropathy is reported to result in tubulointerstitial fibrosis and inflammation.
  
  
  METHODS
  To elucidate possible effects of CAA on extracellular matrix homeostasis, we investigated the action of CAA on markers of extracellular matrix (ECM) homeostasis in human proximal tubule cells (RPTEC) by use of direct ELISA for extracellular collagens and gelatin zymography.
  
  
  RESULTS
  An increase in type III collagen and a decrease in type IV collagen abundance in the media of RPTEC could be observed after exposure to CAA in clinically relevant concentrations. CAA increased intracellular type III and decreased intracellular type IV collagen. MMP-2 activity was decreased but MMP-9 activity unchanged. The enhanced CAA-induced collagen III formation could be attenuated by the intracellular Ca(2+)-chelator BAPTA-AM, the PKA-antagonist H-89 and by extracellular acidification. CAA-induced collagen III abundance was enhanced by db-cAMP and IBMX and by protein overload.
  
  
  CONCLUSIONS
  CAA exerts profibrotic effects on RPTEC dependent on Ca(2+) and cAMP/PKA-signaling. These effects are enhanced by additional protein burden and attenuated by acidification. © 2014 S. Karger AG, Basel.
authors.affiliation: Medizinische Klinik und Poliklinik 2, Universitätsklinikum Großhadern, Ludwig-Maximilians-Universität München, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Benesic
authors.forename: Gerald
authors.initials: G
authors.lastname: Schwerdt
authors.forename: Isabell
authors.initials: I
authors.lastname: Hennemeier
authors.forename: Christoph
authors.initials: C
authors.lastname: Sauvant
authors.forename: Sigrid
authors.initials: S
authors.lastname: Mildenberger
authors.forename: Michael
authors.initials: M
authors.lastname: Gekle
mesh_terms: D000079:Acetaldehyde / Q000031:analogs & derivatives* / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D024061:Collagen Type III / Q000032:analysis / Q000378:metabolism; D024141:Collagen Type IV / Q000032:analysis / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005109:Extracellular Matrix / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007069:Ifosfamide / Q000737:chemistry / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D018906:Antineoplastic Agents, Alkylating; D024061:Collagen Type III; D024141:Collagen Type IV; D007546:Isoquinolines; D013449:Sulfonamides; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; C004656:chloroacetaldehyde; D000242:Cyclic AMP; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D000079:Acetaldehyde; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D002118:Calcium; D007069:Ifosfamide