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

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dc.contributorSistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP
dc.contributor.authorAZEVEDO, Hatylas
dc.contributor.authorRENESTO, Paulo Guilherme
dc.contributor.authorCHINEN, Rogerio
dc.contributor.authorNAKA, Erika
dc.contributor.authorMATOS, Ana Cristina Carvalho de
dc.contributor.authorCENEDEZE, Marcos Antonio
dc.contributor.authorMOREIRA-FILHO, Carlos Alberto
dc.contributor.authorCAMARA, Niels Olsen Saraiva
dc.contributor.authorPACHECO-SILVA, Alvaro
dc.date.accessioned2016-03-14T14:27:06Z
dc.date.available2016-03-14T14:27:06Z
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.
dc.description.indexMEDLINE
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.identifier.citationHUMAN GENOMICS, v.10, article ID 2, 12p, 2016
dc.identifier.doi10.1186/s40246-015-0059-6
dc.identifier.eissn1479-7364
dc.identifier.issn1473-9542
dc.identifier.urihttps://observatorio.fm.usp.br/handle/OPI/13483
dc.language.isoeng
dc.publisherBIOMED CENTRAL LTD
dc.relation.ispartofHuman Genomics
dc.rightsopenAccess
dc.rights.holderCopyright BIOMED CENTRAL LTD
dc.subjectNetwork analysis
dc.subjectKidney transplantation
dc.subjectGenomics
dc.subjectProximal tubular dysfunction
dc.subjectTranscriptional profiling
dc.subject.otherendoplasmic-reticulum stress
dc.subject.othermolecular-weight proteins
dc.subject.otherretinol-binding-protein
dc.subject.otherchronic allograft nephropathy
dc.subject.otherubiquitin-proteasome system
dc.subject.otherkidney-transplant
dc.subject.othermediated rejection
dc.subject.othernetwork
dc.subject.otherautophagy
dc.subject.otherexpression
dc.subject.wosGenetics & Heredity
dc.titleIntragraft transcriptional profiling of renal transplant patients with tubular dysfunction reveals mechanisms underlying graft injury and recovery
dc.typearticle
dc.type.categoryoriginal article
dc.type.versionpublishedVersion
dspace.entity.typePublication
hcfmusp.author.externalRENESTO, Paulo Guilherme:Univ Fed Sao Paulo UNIFESP, Div Nephrol, Lab Clin & Expt Immunol, Sao Paulo, Brazil
hcfmusp.author.externalCHINEN, Rogerio:Univ Fed Sao Paulo UNIFESP, Div Nephrol, Lab Clin & Expt Immunol, Sao Paulo, Brazil; Hosp Albert Einstein, Inst Israelita Ensino & Pesquisa Albert Einstein, Sao Paulo, Brazil
hcfmusp.author.externalNAKA, Erika:Univ Fed Sao Paulo UNIFESP, Div Nephrol, Lab Clin & Expt Immunol, Sao Paulo, Brazil
hcfmusp.author.externalMATOS, Ana Cristina Carvalho de:Univ Fed Sao Paulo UNIFESP, Div Nephrol, Lab Clin & Expt Immunol, Sao Paulo, Brazil; Hosp Albert Einstein, Inst Israelita Ensino & Pesquisa Albert Einstein, Sao Paulo, Brazil
hcfmusp.author.externalCENEDEZE, Marcos Antonio:Univ Fed Sao Paulo UNIFESP, Div Nephrol, Lab Clin & Expt Immunol, Sao Paulo, Brazil
hcfmusp.author.externalCAMARA, Niels Olsen Saraiva:Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Lab Transplantat Immunobiol, Sao Paulo, Brazil; Univ Fed Sao Paulo UNIFESP, Div Nephrol, Lab Clin & Expt Immunol, Sao Paulo, Brazil
hcfmusp.author.externalPACHECO-SILVA, Alvaro:Univ Fed Sao Paulo UNIFESP, Div Nephrol, Lab Clin & Expt Immunol, Sao Paulo, Brazil; Hosp Albert Einstein, Inst Israelita Ensino & Pesquisa Albert Einstein, Sao Paulo, Brazil
hcfmusp.citation.scopus4
hcfmusp.contributor.author-fmusphcHATYLAS FELYPE ZANETI DE AZEVEDO
hcfmusp.contributor.author-fmusphcCARLOS ALBERTO MOREIRA FILHO
hcfmusp.description.articlenumber2
hcfmusp.description.volume10
hcfmusp.origemWOS
hcfmusp.origem.pubmed26742487
hcfmusp.origem.scopus2-s2.0-84954076963
hcfmusp.origem.wosWOS:000367693800002
hcfmusp.publisher.cityLONDON
hcfmusp.publisher.countryENGLAND
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