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Open Access Highly Accessed Research article

Karyopherins: potential biological elements involved in the delayed graft function in renal transplant recipients

Gianluigi Zaza1*, Federica Rascio2, Paola Pontrelli2, Simona Granata1, Patrizia Stifanelli3, Matteo Accetturo2, Nicola Ancona3, Loreto Gesualdo2, Antonio Lupo1 and Giuseppe Grandaliano4

Author Affiliations

1 Renal Unit, Department of Medicine, University-Hospital of Verona, Piazzale A. Stefani 1, 37126 Verona (VR), Italy

2 Renal, Dialysis and Transplant Unit-Department of Emergency and Transplantation, University of Bari, Bari, Italy

3 Istituto studi sui sistemi intelligenti per l′automazione (ISSIA), Consiglio Nazionale delle Ricerche (CNR), Bari, Italy

4 Nephrology, Dialysis and Transplantation Unit, Dept. of Medical and Surgical Sciences, University of Foggia, Foggia, Italy

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BMC Medical Genomics 2014, 7:14  doi:10.1186/1755-8794-7-14

Published: 14 March 2014

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.

Keywords:
Delayed graft function; Renal transplantation; Microarray