Renal Protection by Dopamine Against in vivo Hypothermia/Rewarming Injury Through CBS-induced H2S Production

GJ Dugbartey. University Medical Center Groningen, Groningen, The Netherlands

Introduction: Hypothermic static preservation is commonly applied to preserve organ grafts during transplantation. However, cold ischemia is associated with the induction of renal injury, in which reactive oxygen species (ROS) play a major role. It has been recently reported that cellular uptake of catecholamines prevents hypothermia/rewarming-induced cell death by inhibiting ROS production. Recently, we observed in the ductus deferens cells of the hibernating Syrian hamster that one of the protective mechanisms consists of the endogenous production of hydrogen sulfide (H2S) through the enzyme cystathionine-β-synthase (CBS). We also showed in cultured rat smooth muscle aortic cells that endogenous H2S production can be boosted by administration of dopamine. In this study, we investigated whether these mechanisms are operational in vivo in the rat kidney, by investigating the effect of dopamine on renal injury induced by hypothermia and rewarming.

Methods: Wistar rats (n= 6 per group) were anesthetized with ketamine (i.v.) with or without infusion of dopamine (125 μg/kg/min) and cooled to 15°C core temperature for 3 hours, followed by rewarming to 37°C for 1 hour. The carotid artery was canulated to monitor blood pressure and heart rate throughout the procedure. Rats that did not undergo forced hypothermia served as controls (n=6). Blood samples were taken at several time-points before, during and after the cooling phase, while kidneys were harvested upon euthanization after full rewarming. Renal damage was assessed by measuring serum creatinine levels, levels of ROS production and immunohistochemistry with early damage markers.

Results: Forced hypothermia followed by rewarming of rats led to the induction of glomerular and interstitial injury in animals anesthetized with ketamine, as indicated by histopathological changes, higher KIM-1 expression, influx of neutrophils and macrophages, and ROS generation. Addition of dopamine on the other hand, limited renal hypothermia/rewarming injury in animals anesthetized with ketamine and upregulated CBS expression and subsequent H2S production.

Conclusion: Our results demonstrate that dopamine has renoprotection via CBS-induced H2S production against damage induced by hypothermia/rewarming.

Reference

1. Gottmann U, et al. KI. 2006.

2. Talaei F, et al . PLoS One. 2011.

3. Yard B, et al. AJT. 2004.