Ischemia-Reperfusion Induces Glomerular and Tubular Activation of Proinflammatory and Antiapoptotic Pathways

Loverre, Antonia; Ditonno, Pasquale; Crovace, Antonio; Gesualdo, Loreto; Ranieri, Elena; Pontrelli, Paola; Stallone, Giovanni; Infante, Barbara; Schena, Antonio; Paolo, Salvatore Di; Capobianco, Carmen; Ursi, Michele; Palazzo, Silvano; Battaglia, Michele; Selvaggi, Francesco Paolo; Schena, Francesco Paolo; Grandaliano, Giuseppe

doi:10.1097/01.asn.0000139932.00971.e4

Cited by 92 publications

(71 citation statements)

References 52 publications

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“…NIK phosphorylation in podocytes and tubular cells is increased during human and experimental ischemia reperfusion, although additional events in the noncanonical NF-B pathway are not explored, and, furthermore, NIK activates other signaling pathways. 59 In experimental diabetic nephrop- BRIEF REVIEW www.jasn.org athy, tubular NIK and RelB DNA binding increases. 60 TWEAK-dependent nuclear RelB and p52 and the renal expression of the RelB/p52 gene targets increase in tubular cells during toxic AKI.…”

Section: Nf-b Activation In Experimental and Human Renal Diseasementioning

confidence: 99%

NF-κB in Renal Inflammation

Sanz¹,

Sanchez-Niño²,

Ramos³

et al. 2010

Journal of the American Society of Nephrology

518

379

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Section: Nf-b Activation In Experimental and Human Renal Diseasementioning

confidence: 99%

NF-κB in Renal Inflammation

Sanz¹,

Sanchez-Niño²,

Ramos³

et al. 2010

Journal of the American Society of Nephrology

518

379

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“…We therefore chose to perform a double-fluorescence immunolabeling (27) to quantify the total expression of IRS-1 and IRS-2 proteins and the levels of their activated (tyrosine phosphorylated) forms. In preliminary experiments, we used PBMC from buffycoat byproducts of whole blood that was donated by healthy volunteers to compare the quantification of basal and insulinstimulated IRS tyrosine phosphorylation by immunoblotting with the quantification of signals that were detected by immunocytochemistry.…”

Section: Cell Immunofluorescence and Confocal Laser Scanning Microscopymentioning

confidence: 99%

“…Cells were lysed and subjected to blotting as described (27), with minor modifications. Briefly, aliquots that contained 50 g of proteins from each lysate were subjected to SDS/PAGE on a 10% gel under reducing conditions and then electrotransferred onto a polyvinylidene difluoride membrane (Immun-Blot PVDF Membrane, 0.2 m; BioRad, Milan, Italy) using a semidry Transblot apparatus (BioRad).…”

Section: Western Blottingmentioning

confidence: 99%

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Chronic Inhibition of Mammalian Target of Rapamycin Signaling Downregulates Insulin Receptor Substrates 1 and 2 and AKT Activation

Paolo

Teutonico

Leogrande

et al. 2006

Journal of the American Society of Nephrology

105

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Overactivation of the mammalian target of rapamycin (mTOR) branch downstream of the phosphatidylinositol 3-kinase-AKT pathway critically modulates insulin and growth factor signaling by insulin receptor substrates (IRS). On the basis of in vitro studies, the mTOR inhibitor rapamycin has been reported to lead to enhanced activation of AKT by relieving this feedback inhibition on IRS function. In view of the critical role of AKT in insulin signaling and tumorigenesis, the in vivo expression and activation of this kinase and of IRS-1 and IRS-2 were explored in PBMC of 30 patients who were treated long term with rapamycin. A marked decrease of basal and insulin-stimulated AKT phosphorylation, which correlated with the increase of patients' insulin resistance, and a significant increase of IRS total protein expression, together with a lower (IRS-2) or absent (IRS-1) increase of insulin-induced tyrosine phosphorylation, were found. Therefore, contrary to the expectations, long-term exposure to rapamycin caused the impairment of IRS signaling and AKT activation, and this would help to explain the antiproliferative effect and the possible deterioration of glucose metabolism that are observed in rapamycin-treated patients. These findings may form a novel basis for improved understanding of the role of mTOR inhibition in human diseases, such as diabetes and cancer.

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“…We further postulated that analysis of IRI-implicated genes that are targeted by commonly used immunosuppressive drugs (16) will both identify possible mechanisms of IRI-induced alloimmunity as well as provide clues how these agents alter recovery from IRI. Previous reports on prolonged DGF observed in rapamycin-treated patients (17) and the reduction of IRI by experimental pharmacological preconditioning with FK506 (18) provided focus towards genes associated with calcineurin and mTOR signaling. To test theses hypotheses we utilized a well established murine model of kidney IRI and used current genomic techniques and in-depth computational analysis of molecular responses of kidney tissues to both moderate and severe IRI.…”

Section: Introductionmentioning

confidence: 99%

Genomic Profiling of Kidney Ischemia-Reperfusion Reveals Expression of Specific Alloimmunity-Associated Genes: Linking “Immune” and “Nonimmune” Injury Events

Grigoryev

Liu

Cheadle

et al. 2006

Transplantation Proceedings

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Increased organ ischemia time leads to delayed graft function (DGF), increased acute rejection (AR), enhanced chronic allograft nephropathy (CAN) and reduced long term allograft survival. The mechanisms by which IRI predisposes to AR and CAN are unknown. We hypothesized that gene expression profiling of IRI-affected kidney would identify how IRI predisposes to AR and CAN. Furthermore, we examined how current immunosuppressive drug molecular targets are altered by IRI.C57BL/6J mice were exposed to 30 (n=3) or 60 (n=3) min of bilateral kidney ischemia or sham surgery (n=5). At 36 hr kidney tissue was collected and analyzed using Affymetrix 430MOEA (22626 genes) array and GC-RMA-SAM pipeline. Genes with the false discovery rate (q<1%) and ±50% fold change (FC) were considered affected by IRI. Genes coding for histocompatibility and antigen presenting factors, calcineurin and mTOR pathway-associated proteins were selected using Gene Ontology (GO) analysis. GO analysis identified 10 and 17 alloimmunity-related genes affected by IRI induced by 30 and 60 min of ischemia, respectively including Traf6 (FC=2.99) and H2-D1 (FC=2.58). We also detected significant IRI genomic responses in calcineurin and mTOR pathways represented by Fkbp5 (FC=4.18) and Fkbp1a (FC=2.0); Eif4ebp1 (FC=16.8) and Akt1 (FC=3.64), respectively.These data demonstrated that IRI upregulates expression of several alloimmunity-associated genes, which can in turn enhance alloimune responses. Our discovery of IRI-induced upregulation of genes associated with calcineurin and mTOR pathways are consistent with clinical observations that FK506 and Rapamycin can alter course of DGF. Further validation and dissection of these pathways can lead to novel approaches by which improved management of early "non-immune" transplant events can decrease susceptibility to more classic "immune" changes and CAN.

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Ischemia-Reperfusion Induces Glomerular and Tubular Activation of Proinflammatory and Antiapoptotic Pathways

Cited by 92 publications

References 52 publications

NF-κB in Renal Inflammation

NF-κB in Renal Inflammation

Chronic Inhibition of Mammalian Target of Rapamycin Signaling Downregulates Insulin Receptor Substrates 1 and 2 and AKT Activation

Genomic Profiling of Kidney Ischemia-Reperfusion Reveals Expression of Specific Alloimmunity-Associated Genes: Linking “Immune” and “Nonimmune” Injury Events

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