title: Increased immunogenicity is an integral part of the heat shock response following renal ischemia.
abstract: Renal ischemia increases tubular immunogenicity predisposing to increased risk of kidney allograft rejection. Ischemia-reperfusion not only disrupts cellular homeostasis but also induces the cytoprotective heat shock response that also plays a major role in cellular immune and defense processes. This study therefore tested the hypothesis that upregulation of renal tubular immunogenicity is an integral part of the heat shock response after renal ischemia. Expressions of 70 kDa heat shock protein (Hsp70), major histocompatibility complex (MHC) class II, and intercellular adhesion molecule-1 (ICAM-1) were assessed in normal rat kidney (NRK) cells following ATP depletion (antimycin A for 3 h) and heat (42°C for 24 h). In vitro, transient Hsp70 transfection and heat shock factor-1 (HSF-1) transcription factor decoy treatment were performed. In vivo, ischemic renal cortex was investigated in Sprague-Dawley rats following unilateral renal artery clamping for 45 min and 24 h recovery. Upregulation of Hsp70 was closely and significantly correlated with upregulation of MHC class II and/or ICAM-1 following ATP depletion and heat injury. Bioinformatics analysis searching the TRANSFAC database predicted HSF-1 binding sites in these genes. HSF-1 decoy significantly reduced the expression of immunogenicity markers in stressed NRK cells. In the in vivo rat model of renal ischemia, concordant upregulation of MHC class II molecules and Hsp70 suggests biological relevance of this link. The results demonstrate that upregulation of renal tubular immunogenicity is an integral part of the heat shock response after renal ischemia. Bioinformatic analysis predicted a molecular link to tubular immunogenicity at the level of the transcription factor HSF-1 that was experimentally verified by HSF-1 decoy treatment. Future studies in HSF-1 knockout mice are needed.
authors.affiliation: Department of Pediatrics, Medical University Vienna, Vienna, Austria.
authors.forename: Bettina
authors.initials: B
authors.lastname: Bidmon
authors.forename: Klaus
authors.initials: K
authors.lastname: Kratochwill
authors.forename: Krisztina
authors.initials: K
authors.lastname: Rusai
authors.forename: Lilian
authors.initials: L
authors.lastname: Kuster
authors.forename: Rebecca
authors.initials: R
authors.lastname: Herzog
authors.forename: Oliver
authors.initials: O
authors.lastname: Eickelberg
authors.forename: Christoph
authors.initials: C
authors.lastname: Aufricht
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016208:Databases, Factual; D004195:Disease Models, Animal; D005802:Genes, MHC Class II / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response / Q000276:immunology*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D007511:Ischemia / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000276:immunology / Q000378:metabolism; D008297:Male; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology; D013696:Temperature; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D014157:Transcription Factors; D018799:Intercellular Adhesion Molecule-1; D000255:Adenosine Triphosphate