Aug 30, 2013 - concentrated on arteriolar hyalinosis, arteriolosclerosis and arteriosclerosis. A semi-quantitative rating for each slide ranging from normal (or ...
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ORIGINAL ARTICLE Port J Nephrol Hypert 2013; 27(3): 197-208 Advance Access publication 30 August 2013
Different pathways and biomarkers of acute and chronic cyclosporineinduced nephrotoxicity in a rat model – focus on overexpression of mTOR and Mki67 Diferentes vias de sinalização e biomarcadores da nefrotoxicidade aguda e crónica induzida pela Ciclosporina num modelo de rato – enfoque para a sobreexpressão de mTOR e Mki67 José Sereno1, Paulo Rodrigues-Santos2,3, Helena Vala4,5, Belmiro Parada6, Rui Alves7,8, Edite Teixeira-Lemos4,5, Petronila Rocha-Pereira9, Frederico Teixeira1, Flávio Reis1* 1Laboratory
of Pharmacology & Experimental Therapeutics, IBILI, Faculty of Medicine, University of Coimbra, Portugal; of Immunology, Faculty of Medicine, University of Coimbra, Portugal; 3Immunology and Oncology Laboratory, Centre for Neurosciences and Cell Biology, Coimbra, Portugal; 4ESAV and 5Educational, Technologies and Health Study Centre, Polytechnic Institute of Viseu, Portugal; 6Department of Urology and Renal Transplant and 7Department of Nephrology, CHUC, Coimbra, Portugal; 8University Nephrology Unit, Faculty of Medicine, University of Coimbra, Portugal; 9Research Centre for Health Sciences, Beira Interior University, Covilhã, Portugal. 2Institute
Received for publication: Accepted in revised form:
28/06/2012 30/08/2013
ABSTRACT Calcineurin inhibitors, in particular Cyclosporin A (CsA), remains the cornerstones of immunosuppressive regimens in many transplantation centres worldwide, regardless of drug-induced nephrotoxicity. The pathogenesis of CsA-induced nephropathy remains to be fully elucidated, but seems to be affected by the duration of drug exposure. This study aimed to clarify the molecular pathways involved in acute and chronic CsA-induced nephrotoxicity, focusing on serum, urinary and renal markers. The study comprised 24 male Wistar rats, divided in two models: acute and chronic CsA (5 mg/Kg bw/day) exposure (3 vs 9 weeks) vs matched control groups. The following data was evaluated: blood pressure and heart rate; serum total and non-HDL cholesterol, glucose and insulin; serum and urine creatinine, blood urea nitrogen (BUN), clearances and glomerular filtration rate (GFR); serum, urine and kidney tissue lipid peroxidation, via malondialdehyde (MDA); kidney mRNA expression of proliferative markers (PCNA, TGF-β1, mTOR and Mki67); kidney lesions. CsA has promoted hypertension and tachycardia, which were aggravated with the duration of exposure. Creatinine and BUN clearance and GFR showed early renal dysfunction, accompanied by increase serum creatinine (p
