title: Hypoxia inducible factor 1-alpha (HIF-1 alpha) is induced during reperfusion after renal ischemia and is critical for proximal tubule cell survival.
abstract: Acute tubular necrosis (ATN) caused by ischemia/reperfusion (I/R) during renal transplantation delays allograft function. Identification of factors that mediate protection and/or epithelium recovery could help to improve graft outcome. We studied the expression, regulation and role of hypoxia inducible factor 1-alpha (HIF-1 α), using in vitro and in vivo experimental models of I/R as well as human post-transplant renal biopsies. We found that HIF-1 α is stabilized in proximal tubule cells during ischemia and unexpectedly in late reperfusion, when oxygen tension is normal. Both inductions lead to gene expression in vitro and in vivo. In vitro interference of HIF-1 α promoted cell death and in vivo interference exacerbated tissue damage and renal dysfunction. In pos-transplant human biopsies, HIF-1 α was expressed only in proximal tubules which exhibited normal renal structure with a significant negative correlation with ATN grade. In summary, using experimental models and human biopsies, we identified a novel HIF-1 α induction during reperfusion with a potential critical role in renal transplant.
authors.affiliation: Department of System Disorders and Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Alcalá University, Madrid, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Conde
authors.forename: Laura
authors.initials: L
authors.lastname: Alegre
authors.forename: Ignacio
authors.initials: I
authors.lastname: Blanco-Sánchez
authors.forename: David
authors.initials: D
authors.lastname: Sáenz-Morales
authors.forename: Elia
authors.initials: E
authors.lastname: Aguado-Fraile
authors.forename: Belén
authors.initials: B
authors.lastname: Ponte
authors.forename: Edurne
authors.initials: E
authors.lastname: Ramos
authors.forename: Ana
authors.initials: A
authors.lastname: Sáiz
authors.forename: Carlos
authors.initials: C
authors.lastname: Jiménez
authors.forename: Angel
authors.initials: A
authors.lastname: Ordoñez
authors.forename: Manuel
authors.initials: M
authors.lastname: López-Cabrera
authors.forename: Luis
authors.initials: L
authors.lastname: del Peso
authors.forename: Manuel O
authors.initials: MO
authors.lastname: de Landázuri
authors.forename: Fernando
authors.initials: F
authors.lastname: Liaño
authors.forename: Rafael
authors.initials: R
authors.lastname: Selgas
authors.forename: Jose Antonio
authors.initials: JA
authors.lastname: Sanchez-Tomero
authors.forename: María Laura
authors.initials: ML
authors.lastname: García-Bermejo
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004847:Epithelial Cells / Q000201:enzymology / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D016030:Kidney Transplantation; D007683:Kidney Tubular Necrosis, Acute / Q000150:complications / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010100:Oxygen / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015427:Reperfusion Injury / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014184:Transplantation, Homologous; D055815:Young Adult
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D010100:Oxygen