Activation of the cannabinoid receptor 2 increases renal perfusion

Abstract

Acute kidney injury (AKI) is an increasing clinical problem that is associated with chronic kidney disease progression. Cannabinoid receptor 2 (CB2) activation has been shown to mitigate some of the deleterious tubular effects due to AKI, but its role on the renal vasculature has not been fully described. In this study, we investigated the effects of our novel CB2 receptor agonist, SMM-295, on renal vasculature by assessing cortical perfusion with laser Doppler flowmetry and changes in luminal diameter with isolated afferent arterioles. In this study, intravenously infused SMM-295 (6 mg/kg) significantly increased cortical renal perfusion (13.8 ± 0.6%; P < 0.0001; n = 7) compared with vehicle (0.1 ± 1.5%; n = 10) normalized to baseline values in anesthetized C57BL/6J mice. This effect was not dependent upon activation of the CB1 receptor (met-anandamide; 6 mg/kg iv) and was predominantly abolished in Cnr2 knockout mice with SMM-295 (6 mg/kg iv). Ablation of the renal afferent nerves with capsaicin blocked the SMM-295-dependent increase in renal cortical perfusion, and the increased renal blood flow was not dependent upon products synthesized by cyclooxygenase or nitric oxide synthase. The increased renal perfusion by CB2 receptor activation is also attributed to a direct vascular effect, since SMM-295 (5 μM) engendered a significant 37 ± 7% increase ( P < 0.0001; n = 4) in luminal diameters of norepinephrine-preconstricted afferent arterioles. These data provide new insight into the potential benefit of SMM-295 by activating vascular and nonvascular CB2 receptors to promote renal vasodilation, and provide a new therapeutic target to treat renal injuries that impact renal blood flow dynamics.

Cannabis Use and Risk of Acute Kidney Injury in Patients with Advanced Chronic Kidney Disease Transitioning to Dialysis

“…Conversely, CB 2 receptor activation has an opposing function to CB 1 and elicits protective properties in animal models of AKI, including cisplatin-induced nephrotoxicity 57,58 and renal ischemia-reperfusion injury. [59][60][61] Based on the findings of these above-mentioned preclinical studies, we postulated that the exposure to cannabis and its active ingredients would be associated with an increased risk of kidney injury and progression of CKD. However, our findings did not support this hypothesis.…”

Cannabinoid Receptor 2 (CB2) Inverse Agonist SMM-189 Induces Expression of Endogenous CB2 and Protein Kinase A That Differentially Modulates the Immune Response and Suppresses Experimental Colitis

“…This is in contrast with a report that activation of the CB2 receptor by JWH-133, a CB2 agonist, protects against cerebral ischemia mainly by inhibiting the recruitment of neutrophils [ 48 ]. This may reflect differences in the response to CB2 agonists and inverse agonists in the central nervous system versus the systemic immune cell response [ 49 , 50 ]. NK cells also protect mice from DSS-induced colitis by regulating neutrophil functions, in this case via NKG2A receptors [ 51 ].…”

DNA damage is overcome by TRIP13 overexpression during cisplatin nephrotoxicity

“…The kidney sections were deidentified and scored by a blinded nephrologist with expertise in rodent models of AKI to assess tubular injury. The criteria for damaged tubules included the identification of flattened epithelia, tubular dilation, and cast formation as previously described in our lab (23,25,26,(59)(60)(61). The injured tubules were calculated as a percentage of the total number of tubules counted in 3-5 different sections from every animal in each group.…”