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: Gianluigi Zaza, Federica Rascio, Paola Pontrelli, Simona Granata, Patrizia Stifanelli, Matteo Accetturo, Nicola Ancona, Loreto Gesualdo, Antonio Lupo, Giuseppe Grandaliano
• Journal: BMC medical genomics (BMC Med Genomics) Vol. 7 Pg. 14 (Mar 14 2014) ISSN: 1755-8794 [Electronic] England
• PMID: 24625024 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-6
• Karyopherins
• STAT3 Transcription Factor

Topics

• Cell Nucleus (drug effects, metabolism)
• Delayed Graft Function (etiology, genetics)
• Demography
• Female
• Gene Expression Profiling
• Humans
• Interleukin-6 (pharmacology)
• Karyopherins (genetics, metabolism)
• Kidney Transplantation (adverse effects)
• Leukocytes, Mononuclear (drug effects, metabolism)
• Male
• Middle Aged
• Phosphorylation (drug effects)
• Principal Component Analysis
• Protein Transport (drug effects)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (genetics)
• Transcriptome (genetics)