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

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

Author Azevedo, Hatylas Google Scholar
Renesto, Paulo Guilherme Autor UNIFESP Google Scholar
Chinen, Rogerio Autor UNIFESP Google Scholar
Naka, Erika Autor UNIFESP Google Scholar
Carvalho de Matos, Ana Cristina Autor UNIFESP Google Scholar
Cenedeze, Marcos Antonio Autor UNIFESP Google Scholar
Moreira-Filho, Carlos Alberto Google Scholar
Saraiva Camara, Niels Olsen Autor UNIFESP Google Scholar
Pacheco-Silva, Alvaro Autor UNIFESP Google Scholar
Abstract 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.
Keywords Network Analysis
Kidney Transplantation
Proximal Tubular Dysfunction
Transcriptional ProfilingEndoplasmic-Reticulum Stress
Molecular-Weight Proteins
Chronic Allograft Nephropathy
Ubiquitin-Proteasome System
Mediated Rejection
Language English
Sponsor Fundacao de Amparo a Pesquisa do Estado de Sao Paulo-FAPESP [2009/53443-1, 2011/50761-2, 2012/02270-2]
Conselho Nacional de Desenvolvimento Cientifico e Tecnologico-CNPq [307626/2014-8]
Conselho Nacional de Desenvolvimento Cientifico e Tecnologico-CNPq (INCT Complex Fluids)
NAP e-Science USP
Grant number FAPESP: 2009/53443-1
FAPESP: 2011/50761-2
FAPESP: 2012/02270-2
CNPq: 307626/2014-8
Date 2016
Published in Human Genomics. London, v. 10, 2016.
ISSN 1473-9542 (Sherpa/Romeo, impact factor)
Publisher Bentham Science Publ Ltd
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000367693800002

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