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

Author(s)

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]}

Affiliation

^[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

• Document type: Journal article
• Source: HUMAN GENOMICS; v. 10, JAN 7 2016.
• Web of Science Citations: 1

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. (AU)

• FAPESP's process: 11/50761-2 - Models and methods of e-Science for life and agricultural sciences
• Grantee: Roberto Marcondes Cesar Junior
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 12/02270-2 - New cellular, molecular and immunological mechanisms involved in acute and chronic renal injury: the search for new therapeutical approaches
• Grantee: Niels Olsen Saraiva Câmara
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 09/53443-1 - Neuroimmunology, functional genomics and neuroimaging: an integrated approach for studying physiopathology and treatment in refractory epilepsy
• Grantee: Carlos Alberto Moreira Filho
• Support Opportunities: Research Projects - Thematic Grants