Intragraft transcriptional profiling of renal transplant patients with tubular dysfunction reveals mechanisms underlying graft injury and recovery

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dc.contributor.authorAzevedo, Hatylas
dc.contributor.authorRenesto, Paulo Guilherme [UNIFESP]
dc.contributor.authorChinen, Rogerio [UNIFESP]
dc.contributor.authorNaka, Erika [UNIFESP]
dc.contributor.authorCarvalho de Matos, Ana Cristina [UNIFESP]
dc.contributor.authorCenedeze, Marcos Antonio [UNIFESP]
dc.contributor.authorMoreira-Filho, Carlos Alberto
dc.contributor.authorSaraiva Camara, Niels Olsen [UNIFESP]
dc.contributor.authorPacheco-Silva, Alvaro [UNIFESP]
dc.date.accessioned2019-01-21T10:29:22Z
dc.date.available2019-01-21T10:29:22Z
dc.date.issued2016
dc.description.abstractBackground: Proximal tubular dysfunction (PTD) is associated with a decreased long-term graft survival in renal transplant patients and can be detected by the elevation of urinary tubular proteins. This study investigated transcriptional changes in biopsies from renal transplant patients with PTD to disclose molecular mechanisms underlying graft injury and functional recovery. Methods: Thirty-three renal transplant patients with high urinary levels of retinol-binding protein, a biomarker of PTD, were enrolled in the study. The initial immunosuppressive scheme included azathioprine, cyclosporine, and steroids. After randomization, 18 patients (group 2) had their treatment modified by reducing cyclosporine dosage and substituting azathioprine for mycophenolate mofetil, while the other 15 patients (group 1) remained under the initial scheme. Patients were biopsied at enrollment and after 12 months of follow-up, and paired comparisons were performed between their intragraft gene expression profiles. The differential transcriptome profiles were analyzed by constructing gene co-expression networks and identifying enriched functions and central nodes in each network. Results: Only the alternative immunosuppressive scheme used in group 2 ameliorated renal function and tubular proteinuria after 12 months of follow-up. Intragraft molecular changes observed in group 2 were linked to autophagy, extracellular matrix, and adaptive immunity. Conversely, gene expression changes in group 1 were related to fibrosis, endocytosis, ubiquitination, and endoplasmic reticulum stress. Conclusion: These results suggest that molecular networks associated with the control of endocytosis, autophagy, protein overload, fibrosis, and adaptive immunity may be involved in improvement of graft function.en
dc.description.affiliationDepartment of Pediatrics, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
dc.description.affiliationLaboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, Universidade de São Paulo (USP), São Paulo, Brazil
dc.description.affiliationLaboratory of Clinical and Experimental Immunology, Nephrology Division, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
dc.description.affiliationInstituto Israelita de Ensino e Pesquisa Albert Einstein, Hospital Albert Einstein, São Paulo, Brazil
dc.description.affiliationUnifespLaboratory of Clinical and Experimental Immunology, Nephrology Division, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipFundacao de Amparo a Pesquisa do Estado de Sao Paulo-FAPESP [2009/53443-1, 2011/50761-2, 2012/02270-2]
dc.description.sponsorshipConselho Nacional de Desenvolvimento Cientifico e Tecnologico-CNPq [307626/2014-8]
dc.description.sponsorshipConselho Nacional de Desenvolvimento Cientifico e Tecnologico-CNPq (INCT Complex Fluids)
dc.description.sponsorshipNAP e-Science USP
dc.description.sponsorshipIDFAPESP: 2009/53443-1
dc.description.sponsorshipIDFAPESP: 2011/50761-2
dc.description.sponsorshipIDFAPESP: 2012/02270-2
dc.description.sponsorshipIDCNPq: 307626/2014-8
dc.identifierhttps://doi.org/10.1186/s40246-015-0059-6
dc.identifier.citationHuman Genomics. London, v. 10, 2016.
dc.identifier.doi10.1186/s40246-015-0059-6
dc.identifier.fileWOS000367693800002.pdf
dc.identifier.issn1473-9542
dc.identifier.urihttp://repositorio.unifesp.br/handle/11600/49192
dc.identifier.wosWOS:000367693800002
dc.language.isoeng
dc.publisherBentham Science Publ Ltd
dc.relation.ispartofHuman Genomics
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectNetwork Analysisen
dc.subjectKidney Transplantationen
dc.subjectGenomicsen
dc.subjectProximal Tubular Dysfunctionen
dc.subjectTranscriptional ProfilingEndoplasmic-Reticulum Stressen
dc.subjectMolecular-Weight Proteinsen
dc.subjectRetinol-Binding-Proteinen
dc.subjectChronic Allograft Nephropathyen
dc.subjectUbiquitin-Proteasome Systemen
dc.subjectKidney-Transplanten
dc.subjectMediated Rejectionen
dc.subjectNetworken
dc.subjectAutophagyen
dc.subjectExpressionen
dc.titleIntragraft transcriptional profiling of renal transplant patients with tubular dysfunction reveals mechanisms underlying graft injury and recoveryen
dc.typeinfo:eu-repo/semantics/article
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