title: Fenoldopam preconditioning: role of heme oxygenase-1 in protecting human tubular cells and rodent kidneys against cold-hypoxic injury.
abstract: BACKGROUND
  Kidneys from brain-dead donors are cold preserved until transplanted. However, prolonged cold storage can contribute to allograft failure. Studies suggest that donor preconditioning with dopaminergics may reduce cold-ischemic transplant injury, but whether heme oxygenase (HO)-1 induction is an underlying mechanism is not known.
  
  
  OBJECTIVE
  To test whether preconditioning with fenoldopam (FD) induce HO-1 and protect kidneys against cold storage injury and whether HO-1 plays a role in protection.
  
  
  METHODS
  We used human renal proximal tubular epithelial cells, rat kidney transplants, and HO-1 null mice kidneys.
  
  
  RESULTS
  FD preconditioning of cells for 4 hr significantly protected against cell death from 24-hr cold hypoxia and was associated with a dose-dependent increase in HO-1 expression. In a syngeneic rat kidney transplant model, FD preconditioning for 18 hr markedly increased kidney HO-1 expression and protected kidneys against 24-hr cold-ischemic transplant injury. To test the role of HO-1, renal proximal tubular epithelial cells were treated with HO-1 small interfering RNA, followed by FD-preconditioning. Small interfering RNA inhibited the HO-1 messenger RNA expression and reversed the FD protection. Suspension of kidneys of HO-1 null and wild-type mice preconditioned with FD or saline were subjected to 24- and 48-hr cold storage. N-acetyl glucosaminidase, a specific tubular injury marker, was significantly lower in FD-preconditioned wild-type kidneys, but not in HO-1 null kidneys, suggesting a role for HO-1 in FD's preconditioning.
  
  
  CONCLUSIONS
  Our data suggest HO-1 induction as an underlying mechanism for FD preconditioning and support the idea of testing FD preconditioning in the clinical setting. Studies are required to determine the optimum FD-preconditioning protocol.
authors.affiliation: Nephrology Section, General Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. aksalahudeen@mdanderson.org
authors.forename: Abdulla K
authors.initials: AK
authors.lastname: Salahudeen
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
authors.forename: Hong
authors.initials: H
authors.lastname: Huang
authors.forename: Sylvain
authors.initials: S
authors.lastname: Dore
authors.forename: David E
authors.initials: DE
authors.lastname: Stec
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D050377:Cold Ischemia; D018491:Dopamine Agonists / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D018818:Fenoldopam / Q000494:pharmacology*; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D019194:Ischemic Preconditioning / Q000379:methods*; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology* / Q000293:injuries; D016030:Kidney Transplantation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009926:Organ Preservation / Q000379:methods*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011920:Rats, Inbred WF
chemical_list: D018491:Dopamine Agonists; D034741:RNA, Small Interfering; D051547:Heme Oxygenase-1; D018818:Fenoldopam