Abstract
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. 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. We used human renal proximal tubular epithelial cells, rat kidney transplants, and HO-1 null mice kidneys. 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. 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.
Highlights
In clinical practice, kidneys retrieved from brain-dead donors are cold preserved until transplanted
To test the role of heme oxygenase-1 (HO1), renal proximal tubular epithelial (RPTE) cells were treated with HO1 siRNA, followed by FD-preconditioning. siRNA inhibited the HO1 mRNA expression and reversed the FD protection
Suspension of kidneys of HO1(−/−) null and wild type (WT) mice preconditioned with FD or saline were subjected to 24 and 48 h cold storage
Summary
Kidneys retrieved from brain-dead donors are cold preserved until transplanted. In experimental studies, administration of such compounds was shown to reduce cold storage associated injuries of cells and transplanted kidneys [5, 6]. Since dopaminergic compounds are known to induce HO1 in cell culture studies and deliberate induction of HO1 in in-vivo studies has been shown to protect kidney against acute injuries including that of transplants, we speculated that the preconditioning effect of dopaminergic compounds against cold storage could be arising from its ability to induce HO1 [7,8,9,10,11,12,13,14]. Studies suggest that donor preconditioning with dopaminergics may reduce cold-ischemic transplant injury, but whether heme oxygenase-1 (HO1) induction is an underlying mechanism is not known
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