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. METHOD: 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. CONCLUSION: 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.
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. METHOD: 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. CONCLUSION: 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: K A Nath; G M Vercellotti; J P Grande; H Miyoshi; C V Paya; J C Manivel; J J Haggard; A J Croatt; W D Payne; J Alam Journal: Kidney Int Date: 2001-01 Impact factor: 10.612
Authors: Quansheng Lu; Yu Yang; Van Anthony Villar; Laureano Asico; John E Jones; Peiying Yu; Hewang Li; Edward J Weinman; Gilbert M Eisner; Pedro A Jose Journal: Hypertens Res Date: 2013-02-21 Impact factor: 3.872