title: Conversion to sirolimus ameliorates cyclosporine-induced nephropathy in the rat: focus on serum, urine, gene, and protein renal expression biomarkers.
abstract: Protocols of conversion from cyclosporin A (CsA) to sirolimus (SRL) have been widely used in immunotherapy after transplantation to prevent CsA-induced nephropathy, but the molecular mechanisms underlying these protocols remain nuclear. This study aimed to identify the molecular pathways and putative biomarkers of CsA-to-SRL conversion in a rat model. Four animal groups (n = 6) were tested during 9 weeks: control, CsA, SRL, and conversion (CsA for 3 weeks followed by SRL for 6 weeks). Classical and emergent serum, urinary, and kidney tissue (gene and protein expression) markers were assessed. Renal lesions were analyzed in hematoxylin and eosin, periodic acid-Schiff, and Masson's trichrome stains. SRL-treated rats presented proteinuria and NGAL (serum and urinary) as the best markers of renal impairment. Short CsA treatment presented slight or even absent kidney lesions and TGF-β, NF- κβ, mTOR, PCNA, TP53, KIM-1, and CTGF as relevant gene and protein changes. Prolonged CsA exposure aggravated renal damage, without clear changes on the traditional markers, but with changes in serums TGF- β and IL-7, TBARs clearance, and kidney TGF-β and mTOR. Conversion to SRL prevented CsA-induced renal damage evolution (absent/mild grade lesions), while NGAL (serum versus urine) seems to be a feasible biomarker of CsA replacement to SRL.
authors: Laboratory of Pharmacology & Experimental Therapeutics, IBILI, Faculty of Medicine, University of Coimbra, Sub-Unit 1 (Pólo III), 3000-548 Coimbra, Portugal ; Institute for Nuclear Sciences Applied to Health (ICNAS), University of Coimbra, 3000-548 Coimbra, Portugal.
authors: José
authors: J
authors: Sereno
authors: Laboratory of Pharmacology & Experimental Therapeutics, IBILI, Faculty of Medicine, University of Coimbra, Sub-Unit 1 (Pólo III), 3000-548 Coimbra, Portugal.
authors: Sara
authors: S
authors: Nunes
authors: Institute of Immunology, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal ; Immunology and Oncology Laboratory, Center for Neurosciences and Cell Biology, 3004-504 Coimbra, Portugal.
authors: Paulo
authors: P
authors: Rodrigues-Santos
authors: ESAV, Polytechnic Institute of Viseu, 3504-510 Viseu, Portugal ; Educational, Technologies and Health Study Center, Polytechnic Institute of Viseu, 3504-510 Viseu, Portugal.
authors: Helena
authors: 0000-0001-6829-4867
authors: H
authors: Vala
authors: Research Centre for Health Sciences, Beira Interior University, 6201-506 Covilhã, Portugal.
authors: Petronila
authors: P
authors: Rocha-Pereira
authors: Laboratory of Pharmacology & Experimental Therapeutics, IBILI, Faculty of Medicine, University of Coimbra, Sub-Unit 1 (Pólo III), 3000-548 Coimbra, Portugal ; Biochemistry Department, Pharmacy Faculty, Porto University, 4050-313 Porto, Portugal.
authors: João
authors: J
authors: Fernandes
authors: Biochemistry Department, Pharmacy Faculty, Porto University, 4050-313 Porto, Portugal ; Institute for Molecular and Cellular Biology, Porto University, 4150-180 Porto, Portugal.
authors: Alice
authors: 0000-0002-2565-3169
authors: A
authors: Santos-Silva
authors: Laboratory of Pharmacology & Experimental Therapeutics, IBILI, Faculty of Medicine, University of Coimbra, Sub-Unit 1 (Pólo III), 3000-548 Coimbra, Portugal.
authors: Frederico
authors: F
authors: Teixeira
authors: Laboratory of Pharmacology & Experimental Therapeutics, IBILI, Faculty of Medicine, University of Coimbra, Sub-Unit 1 (Pólo III), 3000-548 Coimbra, Portugal.
authors: Flávio
authors: F
authors: Reis
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood* / Q000652:urine*; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D016572:Cyclosporine / Q000009:adverse effects*; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology; D007668:Kidney / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000097:blood / Q000139:chemically induced* / Q000473:pathology / Q000652:urine; D008297:Male; D018919:Neovascularization, Physiologic; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017208:Rats, Wistar; D020123:Sirolimus / Q000009:adverse effects*
chemical_list: D015415:Biomarkers; D011506:Proteins; D012333:RNA, Messenger; D016572:Cyclosporine; D003094:Collagen; D020123:Sirolimus