title: Bilirubin attenuates the renal tubular injury by inhibition of oxidative stress and apoptosis.
abstract: BACKGROUND
  Bilirubin (BIL) has been recognized as an endogenous antioxidant that shows a protective effect for cardiorenal diseases. We investigated whether administration of BIL had a protective effect on cyclosporine (CsA)-induced nephropathy (CIN), and examined the effects of BIL on the oxidative stress and apoptosis.
  
  
  METHODS
  BIL was pretreated intraperitoneally three times for a week (60 mg/kg), and CsA was injected for 4 weeks (15 mg/kg/day, subcutaneous). Proximal tubular epithelial (HK2) cells were pretreated with 0.1mg/ml of BIL for 24 hours, and then treated with 20 μM of CsA for another 24 hours.
  
  
  RESULTS
  CsA induced marked increases in urine kidney injury molecule-1 (Kim-1) and neutrophil gelatinase-associated lipocalin (NGAL) concentrations (P < 0.05). BIL reduced urine Kim-1 in CIN (P < 0.05), while urine NGAL exhibited a decreasing tendency. In CsA-treated rat kidneys, the protein expression of NOX4 and p22phox was reduced by BIL (P < 0.05). BIL ameliorated CsA-induced arteriolopathy, tubulointerstitial fibrosis, tubular injury, and the apoptosis examined by TUNEL assay (P < 0.01). In HK2 cells, BIL reduced intracellular reactive oxygen species in CsA-treated cells. CsA increased the protein expression of bax, cleaved caspase-9, caspase-3 and the activity of caspase-3; however, the anti-apoptotic bcl-2 protein was reduced. These changes were recovered by BIL (P < 0.05).
  
  
  CONCLUSIONS
  The direct administration of BIL protected against CsA-induced tubular injury via inhibition of oxidative stress and apoptosis.
authors.affiliation: Department of Internal Medicine, Eulji General Hospital, Eulji University College of Medicine, Seoul, Korea.
authors.forename: Se Won
authors.initials: SW
authors.lastname: Oh
authors.forename: Eun Seong
authors.initials: ES
authors.lastname: Lee
authors.forename: Sejoong
authors.initials: S
authors.lastname: Kim
authors.forename: Ki Young
authors.initials: KY
authors.lastname: Na
authors.forename: Dong Wan
authors.initials: DW
authors.lastname: Chae
authors.forename: Suhnggwon
authors.initials: S
authors.lastname: Kim
authors.forename: Ho Jun
authors.initials: HJ
authors.lastname: Chin
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001663:Bilirubin / Q000008:administration & dosage*; D002460:Cell Line; D006801:Humans; D007274:Injections, Intraperitoneal; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001663:Bilirubin