Please use this identifier to cite or link to this item: https://hdl.handle.net/10316/109458
Title: Transition from cyclosporine-induced renal dysfunction to nephrotoxicity in an in vivo rat model
Authors: Sereno, José 
Rodrigues-Santos, Paulo 
Vala, Helena
Rocha-Pereira, Petronila 
Alves, Rui
Fernandes, João
Santos-Silva, Alice
Carvalho, Eugenia 
Teixeira, Frederico 
Reis, F. 
Keywords: Cyclosporin A; transition from dysfunction to nephrotoxicity; biomarkers; fibrosis; proliferation; animal model
Issue Date: 20-May-2014
Publisher: MDPI
Project: SFRH/BD/63962/2009 
SFRH/BD/63962/2009 
PEST-C/SAU/UI3282/2011 
Grant from Sociedade Portuguesa de Diabetologia 
Serial title, monograph or event: International Journal of Molecular Sciences
Volume: 15
Issue: 5
Abstract: Cyclosporin A (CsA), a calcineurin inhibitor, remain the cornerstone of immunosuppressive regimens, regardless of nephrotoxicity, which depends on the duration of drug exposure. The mechanisms and biomarkers underlying the transition from CsA-induced renal dysfunction to nephrotoxicity deserve better elucidation, and would help clinical decisions. This study aimed to clarify these issues, using a rat model of short- and long-term CsA (5 mg/kg bw/day) treatments (3 and 9 weeks, respectively). Renal function was assessed on serum and urine; kidney tissue was used for histopathological characterization and gene and/or protein expression of markers of proliferation, fibrosis and inflammation. In the short-term, creatinine and blood urea nitrogen (BUN) levels increased and clearances decreased, accompanied by glomerular filtration rate (GFR) reduction, but without kidney lesions; at that stage, CsA exposure induced proliferating cell nuclear antigen (PCNA), transforming growth factor beta 1 (TGF-β1), factor nuclear kappa B (NF-κβ) and Tumor Protein P53 (TP53) kidney mRNA up-regulation. In the long-term treatment, renal dysfunction data was accompanied by glomerular and tubulointerstitial lesions, with remarkable kidney mRNA up-regulation of the mammalian target of rapamycin (mTOR) and the antigen identified by monoclonal antibody Ki-67 (Mki67), accompanied by mTOR protein overexpression. Transition from CsA-induced renal dysfunction to nephrotoxicity is accompanied by modification of molecular mechanisms and biomarkers, being mTOR one of the key players for kidney lesion evolution, thus suggesting, by mean of molecular evidences, that early CsA replacement by mTOR inhibitors is indeed the better therapeutic choice to prevent chronic allograft nephropathy.
URI: https://hdl.handle.net/10316/109458
ISSN: 1422-0067
DOI: 10.3390/ijms15058979
Rights: openAccess
Appears in Collections:I&D ICNAS - Artigos em Revistas Internacionais
I&D IBILI - Artigos em Revistas Internacionais
I&D CNC - Artigos em Revistas Internacionais

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