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

Zaza G, Rascio F, Pontrelli P, Granata S, Stifanelli P, Accetturo M, Ancona N, Gesualdo L, Lupo A, Grandaliano G - BMC Med Genomics (2014)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Renal Unit, Department of Medicine, University-Hospital of Verona, Piazzale A, Stefani 1, 37126 Verona (VR), Italy. gianluigi.zaza@univr.it.

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.

Show MeSH

Related in: MedlinePlus

Principal components analysis (PCA) discriminating renal transplant patients with delayed graft function (DGF) from early graft function (EGF) at the time of transplantation (T0) (A) and 24 hours after transplantation (T24) (B) using the expression level of the genes included in the NLS-bearing substrate import into nucleus pathway. Both PCA plots were built using the expression level of all 13 genes included in the NLS-bearing substrate import into nucleus pathway. Red dots indicate patients that developed DGF after transplantation and green dots those with EGF. PCA clearly discriminated in three dimensional space the two study groups at both time points.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC3975142&req=5

Figure 1: Principal components analysis (PCA) discriminating renal transplant patients with delayed graft function (DGF) from early graft function (EGF) at the time of transplantation (T0) (A) and 24 hours after transplantation (T24) (B) using the expression level of the genes included in the NLS-bearing substrate import into nucleus pathway. Both PCA plots were built using the expression level of all 13 genes included in the NLS-bearing substrate import into nucleus pathway. Red dots indicate patients that developed DGF after transplantation and green dots those with EGF. PCA clearly discriminated in three dimensional space the two study groups at both time points.

Mentions: Principal component analysis using the expression level of all 13 genes included in the NLS-bearing substrate import into nucleus pathway was able to clearly discriminate in three dimensional space DGF from EGF at both T0 (Figure 1A) and T24 (Figure 1B).


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

Zaza G, Rascio F, Pontrelli P, Granata S, Stifanelli P, Accetturo M, Ancona N, Gesualdo L, Lupo A, Grandaliano G - BMC Med Genomics (2014)

Principal components analysis (PCA) discriminating renal transplant patients with delayed graft function (DGF) from early graft function (EGF) at the time of transplantation (T0) (A) and 24 hours after transplantation (T24) (B) using the expression level of the genes included in the NLS-bearing substrate import into nucleus pathway. Both PCA plots were built using the expression level of all 13 genes included in the NLS-bearing substrate import into nucleus pathway. Red dots indicate patients that developed DGF after transplantation and green dots those with EGF. PCA clearly discriminated in three dimensional space the two study groups at both time points.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3975142&req=5

Figure 1: Principal components analysis (PCA) discriminating renal transplant patients with delayed graft function (DGF) from early graft function (EGF) at the time of transplantation (T0) (A) and 24 hours after transplantation (T24) (B) using the expression level of the genes included in the NLS-bearing substrate import into nucleus pathway. Both PCA plots were built using the expression level of all 13 genes included in the NLS-bearing substrate import into nucleus pathway. Red dots indicate patients that developed DGF after transplantation and green dots those with EGF. PCA clearly discriminated in three dimensional space the two study groups at both time points.
Mentions: Principal component analysis using the expression level of all 13 genes included in the NLS-bearing substrate import into nucleus pathway was able to clearly discriminate in three dimensional space DGF from EGF at both T0 (Figure 1A) and T24 (Figure 1B).

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Renal Unit, Department of Medicine, University-Hospital of Verona, Piazzale A, Stefani 1, 37126 Verona (VR), Italy. gianluigi.zaza@univr.it.

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.

Show MeSH
Related in: MedlinePlus