title: Karyopherins: potential biological elements involved in the delayed graft function in renal transplant recipients.
abstract: BACKGROUND
  Immediately after renal transplantation, patients experience rapid and significant improvement of their clinical conditions and undergo considerable systemic and cellular modifications. However, some patients present a slow recovery of the renal function commonly defined as delayed graft function (DGF). Although clinically well characterized, the molecular mechanisms underlying this condition are not totally defined, thus, we are currently missing specific clinical markers to predict and to make early diagnosis of this event.
  
  
  METHODS
  We investigated, using a pathway analysis approach, the transcriptomic profile of peripheral blood mononuclear cells (PBMC) from renal transplant recipients with DGF and with early graft function (EGF), before (T0) and 24 hours (T24) after transplantation.
  
  
  RESULTS
  Bioinformatics/statistical analysis showed that 15 pathways (8 up-regulated and 7 down-regulated) and 11 pathways (5 up-regulated and 6 down-regulated) were able to identify DGF patients at T0 and T24, respectively. Interestingly, the most up-regulated pathway at both time points was NLS-bearing substrate import into nucleus, which includes genes encoding for several subtypes of karyopherins, a group of proteins involved in nucleocytoplasmic transport. Signal transducers and activators of transcription (STAT) utilize karyopherins-alpha (KPNA) for their passage from cytoplasm into the nucleus. In vitro functional analysis demonstrated that in PBMCs of DGF patients, there was a significant KPNA-mediated nuclear translocation of the phosphorylated form of STAT3 (pSTAT3) after short-time stimulation (2 and 5 minutes) with interleukin-6.
  
  
  CONCLUSIONS
  Our study suggests the involvement, immediately before transplantation, of karyopherin-mediated nuclear transport in the onset and development of DGF. Additionally, it reveals that karyopherins could be good candidates as potential DGF predictive clinical biomarkers and targets for pharmacological interventions in renal transplantation. However, because of the low number of patients analyzed and some methodological limitations, additional studies are needed to validate and to better address these points.
authors.affiliation: Renal Unit, Department of Medicine, University-Hospital of Verona, Piazzale A, Stefani 1, 37126 Verona (VR), Italy. gianluigi.zaza@univr.it.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Zaza
authors.forename: Federica
authors.initials: F
authors.lastname: Rascio
authors.forename: Paola
authors.initials: P
authors.lastname: Pontrelli
authors.forename: Simona
authors.initials: S
authors.lastname: Granata
authors.forename: Patrizia
authors.initials: P
authors.lastname: Stifanelli
authors.forename: Matteo
authors.initials: M
authors.lastname: Accetturo
authors.forename: Nicola
authors.initials: N
authors.lastname: Ancona
authors.forename: Loreto
authors.initials: L
authors.lastname: Gesualdo
authors.forename: Antonio
authors.initials: A
authors.lastname: Lupo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Grandaliano
mesh_terms: D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D051799:Delayed Graft Function / Q000209:etiology* / Q000235:genetics*; D003710:Demography; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D028884:Karyopherins / Q000235:genetics / Q000378:metabolism*; D016030:Kidney Transplantation / Q000009:adverse effects*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D025341:Principal Component Analysis; D021381:Protein Transport / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D059467:Transcriptome / Q000235:genetics
chemical_list: D015850:Interleukin-6; D028884:Karyopherins; D050796:STAT3 Transcription Factor