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

Autor(es)

Azevedo, Hatylas ^[1] ; Renesto, Paulo Guilherme ^[2] ; Chinen, Rogerio ^{[2, 3]} ; Naka, Erika ^[2] ; Carvalho de Matos, Ana Cristina ^{[2, 3]} ; Cenedeze, Marcos Antonio ^[2] ; Moreira-Filho, Carlos Alberto ^[1] ; Saraiva Camara, Niels Olsen ^{[4, 2]} ; Pacheco-Silva, Alvaro ^{[2, 3]}

Afiliação do(s) autor(es)

^[1] FMUSP, Dept Pediat, Sao Paulo - Brazil

^[2] Univ Fed Sao Paulo UNIFESP, Div Nephrol, Lab Clin & Expt Immunol, Sao Paulo - Brazil

^[3] Hosp Albert Einstein, Inst Israelita Ensino & Pesquisa Albert Einstein, Sao Paulo - Brazil

^[4] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Lab Transplantat Immunobiol, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: HUMAN GENOMICS; v. 10, JAN 7 2016.
• Citações Web of Science: 1

Resumo

Background: 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. (AU)

• Processo FAPESP: 11/50761-2 - Modelos e métodos de e-Science para ciências da vida e agrárias
• Beneficiário: Roberto Marcondes Cesar Junior
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 12/02270-2 - Novos mecanismos celulares, moleculares e imunológicos das lesões renais agudas e crônicas: busca por novas estratégias terapêuticas
• Beneficiário: Niels Olsen Saraiva Câmara
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 09/53443-1 - Neuroimunologia, genômica funcional e neuroimagem: uma abordagem integrada no estudo da fisiopatologia e tratamento da epilepsia refratária
• Beneficiário: Carlos Alberto Moreira Filho
• Modalidade de apoio: Auxílio à Pesquisa - Temático