Cannabidiol treatment ameliorates ischemia/reperfusion renal injury in rats

Abstract

Aims

To investigate the protective effect of cannabidiol, the major non-psychotropic Cannabis constituent, against renal ischemia/reperfusion injury in rats.

Main methods

Bilateral renal ischemia was induced for 30 min followed by reperfusion for 24 h. Cannabidiol (5 mg/kg, i.v.) was given 1 h before and 12 h following the procedure.

Key findings

Ischemia/reperfusion caused significant elevations of serum creatinine and renal malondialdehyde and nitric oxide levels, associated with a significant decrease in renal reduced glutathione. Cannabidiol significantly attenuated the deterioration in the measured biochemical parameters induced by ischemia/reperfusion. Histopathological examination showed that cannabidiol ameliorated ischemia/reperfusion-induced kidney damage. Immunohistochemical analysis revealed that cannabidiol significantly reduced the expression of inducible nitric oxide synthase, tumor necrosis factor-α, cyclooxygenase-2, nuclear factor-κB, Fas ligand and caspase-3, and increased the expression of survivin in ischemic/reperfused kidney tissue.

Significance

Cannabidiol, via its antioxidant and anti-inflammatory properties, may represent a potential therapeutic option to protect against ischemia/reperfusion renal injury.

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.