title: Mechanism of tacrolimus-induced chronic renal fibrosis following transplantation is regulated by ox-LDL and its receptor, LOX-1.
abstract: Chronic renal allograft dysfunction (CRAD) is the most common cause of graft failure following renal transplantation. However, the underlying mechanisms remain to be fully elucidated. Immunosuppressants and hyperlipidemia are associated with renal fibrosis following long‑term use. The present study aimed to determine the effects of tacrolimus (FK506) and lipid metabolism disorder on CRAD. In vitro and in vivo models were used for this investigation. Cells of the mouse proximal renal tubular epithelial cell strain, NRK‑52E, were cultured either with oxidized low‑density lipoprotein (ox‑LDL), FK506, ox‑LDL combined with FK506, or vehicle, respectively. Changes in cell morphology and changes in the levels of lectin‑like ox‑LDL receptor‑1 (LOX‑1), reactive oxygen species (ROS), hydrogen peroxide and fibrosis‑associated genes were evaluated at 24, 48 and 72 h. In separate experiment, total of 60 Sprague‑Dawley rats were divided randomly into four groups, which included a high‑fat group, FK506 group, high‑fat combined with FK506 group, and control group. After 2, 4 and 8 weeks, the serum lipid levels, the levels of ox‑LDL, ROS, and the expression levels of transforming growth factor (TGF)‑β1 and connective tissue growth factor were determined. The in vitro and in vivo models revealed that lipid metabolism disorder and FK506 caused oxidative stress and a fibrogenic response. In addition, decreased levels of LOX‑1 markedly reduced the levels of TGF‑β1 in the in vitro model. Taken together, FK506 and dyslipidemia were found to be associated with CRAD following transplantation.
authors.affiliation: Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Shi
authors.initials: S
authors.lastname: Deng
authors.affiliation: Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Jin
authors.affiliation: Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Bu
authors.affiliation: Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
mesh_terms: D064591:Allografts / Q000473:pathology; D000818:Animals; D055513:Connective Tissue Growth Factor / Q000235:genetics; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000235:genetics / Q000503:physiopathology; D005355:Fibrosis / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007676:Kidney Failure, Chronic / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology; D016030:Kidney Transplantation / Q000009:adverse effects*; D050356:Lipid Metabolism / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000378:metabolism; D051379:Mice; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000096:biosynthesis / Q000235:genetics*; D016559:Tacrolimus / Q000009:adverse effects; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D007166:Immunosuppressive Agents; D008077:Lipoproteins, LDL; C495136:OLR1 protein, rat; D017382:Reactive Oxygen Species; D051127:Scavenger Receptors, Class E; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; C099252:oxidized low density lipoprotein; D055513:Connective Tissue Growth Factor; D016559:Tacrolimus