PMID- 24853130 OWN - NLM STAT- MEDLINE DCOM- 20150106 LR - 20211203 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 15 IP - 5 DP - 2014 May 20 TI - Transition from cyclosporine-induced renal dysfunction to nephrotoxicity in an in vivo rat model. PG - 8979-97 LID - 10.3390/ijms15058979 [doi] AB - 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-beta1), factor nuclear kappa B (NF-kappabeta) 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. FAU - Sereno, Jose AU - Sereno J AD - Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra 3000-548, Portugal. jose6sereno@hotmail.com. FAU - Rodrigues-Santos, Paulo AU - Rodrigues-Santos P AD - Institute of Immunology, Faculty of Medicine, University of Coimbra, Coimbra 3004-504, Portugal. psantos@ci.uc.pt. FAU - Vala, Helena AU - Vala H AD - Agrarian School of Viseu (ESAV), Polytechnic Institute of Viseu, Viseu 3500-606, Portugal. hvala2@gmail.com. FAU - Rocha-Pereira, Petronila AU - Rocha-Pereira P AD - Research Center for Health Sciences, Beira Interior University, Covilha 6201-506, Portugal. petronila@live.com.pt. FAU - Alves, Rui AU - Alves R AD - University Nephrology Unit, Faculty of Medicine, University of Coimbra, Coimbra 3004-504, Portugal. ruimbalves@hotmail.com. FAU - Fernandes, Joao AU - Fernandes J AD - Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra 3000-548, Portugal. jfernandes@email.com. FAU - Santos-Silva, Alice AU - Santos-Silva A AD - Biochemistry Department, Pharmacy Faculty, Porto University, Porto 4050-313, Portugal. assilva@ff.up.pt. FAU - Carvalho, Eugenia AU - Carvalho E AD - Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra 3000-548, Portugal. genita67@gmail.com. FAU - Teixeira, Frederico AU - Teixeira F AD - Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra 3000-548, Portugal. fredjt@ci.uc.pt. FAU - Reis, Flavio AU - Reis F AD - Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra 3000-548, Portugal. freis@fmed.uc.pt. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140520 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Biomarkers) RN - 0 (Cytokines) RN - 0 (Immunosuppressive Agents) RN - 0 (Inflammation Mediators) RN - 0 (RNA, Messenger) RN - 83HN0GTJ6D (Cyclosporine) RN - AYI8EX34EU (Creatinine) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Biomarkers/metabolism MH - Blood Urea Nitrogen MH - Creatinine/blood MH - Cyclosporine/adverse effects/*toxicity MH - Cytokines/genetics/metabolism MH - Disease Models, Animal MH - Immunosuppressive Agents/adverse effects/*toxicity MH - Inflammation Mediators/metabolism MH - Kidney/*drug effects/metabolism/physiopathology MH - Kidney Diseases/*etiology/metabolism/pathology MH - Male MH - RNA, Messenger/metabolism MH - Rats MH - Rats, Wistar MH - TOR Serine-Threonine Kinases/genetics/metabolism MH - Up-Regulation/drug effects PMC - PMC4057770 EDAT- 2014/05/24 06:00 MHDA- 2015/01/07 06:00 PMCR- 2014/05/01 CRDT- 2014/05/24 06:00 PHST- 2014/04/07 00:00 [received] PHST- 2014/05/05 00:00 [revised] PHST- 2014/05/13 00:00 [accepted] PHST- 2014/05/24 06:00 [entrez] PHST- 2014/05/24 06:00 [pubmed] PHST- 2015/01/07 06:00 [medline] PHST- 2014/05/01 00:00 [pmc-release] AID - ijms15058979 [pii] AID - ijms-15-08979 [pii] AID - 10.3390/ijms15058979 [doi] PST - epublish SO - Int J Mol Sci. 2014 May 20;15(5):8979-97. doi: 10.3390/ijms15058979.