Cannabidiol treatment ameliorates ischemia/reperfusion renal injury in rats
Introduction
Renal ischemia/reperfusion injury which occurs during renal transplantation, shock, and kidney resections, is a major cause for acute renal failure with increased morbidity and mortality. It has been estimated that ischemic insult, especially during renal transplantation, is responsible for 20–30% primary graft dysfunction (Ploeg et al., 1992). Reperfusion of ischemic renal tissue initiates a complex series of cellular events that eventually leads to necrotic and apoptotic renal cell death. The exact molecular mechanisms underlying ischemia/reperfusion renal injury are not fully understood. Several factors contribute to the pathogenesis of ischemia/reperfusion injury including ATP depletion, phospholipase and protease activation, increased endothelin-1 formation and neutrophil infiltration (Edelstein et al., 1997). However, increased generation of reactive oxygen species and pro-inflammatory mediators in the reperfusion phase seems to play a crucial role. Also, several antioxidants and anti-inflammatory agents were effective in attenuating renal injury resulting from ischemia/reperfusion (Feng et al., 2011, Hosseini et al., 2010, Kizilgun et al., 2011, Yamamoto et al., 2011).
Cannabidiol is the major non-psychoactive cannabinoid component derived from the plant Cannabis sativa. It possesses powerful antioxidant and anti-inflammatory activities. However, the exact mechanisms of action of cannabidiol remain obscure. In contrast to the other cannabinoids, cannabidiol is known to have a very low affinity for the cannabinoid CB1 and CB2 receptors. The antioxidant and anti-inflammatory effects of cannabidiol may be due to its direct action or mediated through a new cannabinoid, non-CB1 and non-CB2, receptor (Begg et al., 2005, De Petrocellis and Di Marzo, 2010). Cannabidiol may also exert its beneficial effects by inhibiting adenosine uptake and activating transient receptor potential vanilloid-1 (Bisogno et al., 2001, Carrier et al., 2006). Previous reports proved that cannabidiol may have therapeutic utility in a number of conditions involving inflammation and oxidative stress, as diabetes mellitus, rheumatoid arthritis and neurodegenerative disorders (Blake et al., 2006, Iuvone et al., 2009, Rajesh et al., 2010). The protective effect of cannabidiol was also demonstrated in animal models with cerebral, myocardial and liver ischemia/reperfusion (Alvarez et al., 2008, Mukhopadhyay et al., 2011, Walsh et al., 2010). However, to the best of our knowledge, its protective effect against ischemia/reperfusion renal injury was not yet studied.
Therefore, the present study was conducted to evaluate the nephroprotective effect of cannabidiol in rats exposed to bilateral kidney ischemia/reperfusion. Also, the possible mechanisms underlying this effect were investigated.
Section snippets
Drugs
Cannabidiol (Cayman Chemical Company, USA) was dissolved in a vehicle solution of 1% Tween 80 and 2% DMSO in saline. The dose of cannabidiol used in this study was selected based on our preliminary experiments and in accordance with previous reports (Durst et al., 2007).
Animals and treatments
Male Sprague–Dawley rats, weighing 250 ± 10 g were obtained from the Animal House, College of Medicine, King Faisal University. The animals were kept at standard housing facilities (24 ± 1 °C, 45 ± 5% humidity and 12 h light/dark cycle).
Effects of cannabidiol on the measured biochemical parameters
Significant elevations of serum creatinine, renal MDA and NO, associated with a significant decrease in renal GSH were observed in rats exposed to ischemia/reperfusion kidney injury as compared to the sham-operated control group. Cannabidiol treatment resulted in a significant reduction of serum creatinine, and suppressed lipid peroxidation. The GSH depletion and NO increase induced by ischemia/reperfusion were attenuated by cannabidiol treatment, however, their concentrations remained
Discussion
The present study showed that cannabidiol treatment provided a significant nephroprotective effect in rats exposed to ischemia/reperfusion renal injury. In accordance with previous studies, the present one demonstrated that enhanced lipid peroxidation, depletion of antioxidant defenses and increased production of pro‐inflammatory cytokines are implicated in the pathogenesis of kidney injury induced by ischemia/reperfusion (Feng et al., 2011, Hosseini et al., 2010, Kizilgun et al., 2011,
Conclusion
The present results indicate that cannabidiol treatment significantly protected against ischemia/reperfusion kidney injury in rats. The antioxidant, anti-inflammatory and antiapoptotic activities can be considered the main factors responsible for the nephroprotective effect of cannabidiol. Therefore, cannabidiol may be a candidate to protect against kidney tissue injury and dysfunction induced by ischemia/reperfusion.
Conflict of interest statement
The authors declare that there are no conflicts of interest.
Acknowledgments
We would like to thank Mr. Husain Al-Nwuser, technician of the Pharmacology Lab., and Mr. Mohamed Al-Hejab, technician of the Pathology Lab., at College of Medicine, King Faisal University for their kind assistance while performing this study.
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