title: Delayed treatment with oleanolic acid attenuates tubulointerstitial fibrosis in chronic cyclosporine nephropathy through Nrf2/HO-1 signaling.
abstract: BACKGROUND
  Nuclear factor erythroid-2-related factor-2 (Nrf2) is known to protect against tissue injury by orchestrating antioxidant and detoxification responses to oxidative stress. This study investigated whether upregulation of Nrf2-dependent signaling by oleanolic acid (OA), which is known to activate Nrf2, could attenuate renal inflammation and fibrosis in cyclosporine (CsA)-induced kidney injury.
  
  
  METHODS
  Male ICR mice were divided into four treatment groups: Vehicle (VH, n = 6), VH + OA (n = 6), CsA (n = 8), and CsA + OA (n = 8). For the OA-treated groups, OA (25 mg/kg/day) was administered by intraperitoneal injection for the final week of the 4-week experimental period. Renal function, morphologies and signaling were evaluated at the end of the study.
  
  
  RESULTS
  Treatment with CsA resulted in decreased kidney function and urine osmolality and increased urine volume and urinary albumin levels. The CsA-induced changes were improved by OA treatment. Specifically, administration of OA decreased tubulointerstitial fibrosis and inflammation scores that were increased in CsA-treated mice. Furthermore, OA treatment decreased urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-epi-prostaglandin F2α (8-iso-PGF2α) levels. The beneficial effects of OA were attributed to an increased ratio of nuclear/total Nrf2 and subsequently enhanced expression of heme oxygenase (HO)-1, as well as a stable level of Kelch-like ECH-associated protein 1 (Keap1) expression, indicating that OA enhanced nuclear translocation of Nrf2. Increased apoptotic cell death and a high ratio of B cell leukaemia/lymphoma 2 (Bcl-2)-associated X protein (Bax) to Bcl-2 in CsA-treated mice were also significantly ameliorated by OA treatment.
  
  
  CONCLUSIONS
  Our results suggest that OA activates Nrf2/HO-1 signaling in chronic CsA nephropathy, which may have beneficial effects on inflammation and oxidative stress.
authors.forename: Yu Ah
authors.initials: YA
authors.lastname: Hong
authors.forename: Ji Hee
authors.initials: JH
authors.lastname: Lim
authors.forename: Min Young
authors.initials: MY
authors.lastname: Kim
authors.forename: Eun Nim
authors.initials: EN
authors.lastname: Kim
authors.forename: Eun Sil
authors.initials: ES
authors.lastname: Koh
authors.forename: Seok Joon
authors.initials: SJ
authors.lastname: Shin
authors.forename: Bum Soon
authors.initials: BS
authors.lastname: Choi
authors.forename: Cheol Whee
authors.initials: CW
authors.lastname: Park
authors.forename: Yoon Sik
authors.initials: YS
authors.lastname: Chang
authors.affiliation: Department of Internal Medicine, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seoul 137-701, Republic of Korea. sungjin.chung@outlook.com.
authors.forename: Sungjin
authors.initials: S
authors.lastname: Chung
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D016572:Cyclosporine / Q000009:adverse effects*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005355:Fibrosis; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D007674:Kidney Diseases / Q000139:chemically induced* / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D007677:Kidney Function Tests; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009828:Oleanolic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000975:Antioxidants; D015415:Biomarkers; D003598:Cytoskeletal Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D019253:Proto-Oncogene Proteins c-bcl-2; D008315:Malondialdehyde; D009828:Oleanolic Acid; D016572:Cyclosporine; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse