A study by Jenkin et al.revealed a role of CB2 receptor activation in reducing the progression of obesity-related kidney dysfunction by decreasing proteinuria, creatinine clearance, and renal fibrotic markers. In contrast, ZDF rats treated with a CB1 inverse agonist showed improved renal structure and function.Surprisingly, these rats also displayed a marked increase in body weight compared with the weight stability of control mice, which was thought to be due to the development of extreme hyperglycemia in vehicle-treated controls.In a separate study, CB1 antagonism was shown to decrease albuminuria, reduce mesangial expansion, and ameliorate the expression of profibrotic and proinflammatory kidney proteins in lean and obese diabetic mouse models.These findings suggest that the consequences of CB1 modulation in diabetes can differ based on the experimental model, presence of obesity, and presence of hyperglycemia. In other studies that utilized rats with diet-induced obesity, CB1 receptor expression in the kidney is notably upregulated, and treatment with a CB1 receptor antagonist reduced weight, systolic blood pressure, plasma leptin, albuminuria, and plasma creatinine levels. This is associated with the amelioration of glomerulopathy.Furthermore, studies using obese Zucker rats demonstrated that the CB1 inverse agonist, rimonabant, ameliorated proteinuria in an animal model of obesity induced nephropathy.Treatment with rimonabant partially restored creatinine clearance, reduced glomerulosclerosis and tubular-interstitial fibrosis,indoor cannabis growing and lowered tubular damage and renal hypertrophy.It should also be noted that these findings may have been mediated by the effects of rimonabant and not related to the EC system.
While obesity in fa/fa Zucker rats is caused by a mutation of the leptin receptor, rimonabant acts to increase leptin uptake by the kidney, which has been shown to reduce proximal tubule metabolic activity.Therefore, improvement in renal function in these rats may have occurred due to mechanisms related to leptin’s role in proximal tubule cell metabolism,as opposed to a direct action on the EC system. Using a novel mouse strain lacking CB1 receptors in renal proximal tubule cells, Udi et al.found that CB1 receptor deletion did not protect the mice from the deleterious metabolic effects associated with obesity, but significantly diminished obesity-induced lipid accumulation in the kidney. Furthermore, the stimulation of CB1 receptors in renal proximal tubule cells was found to be associated with decreased activation of liver kinase B1 and decreased activity of AMP-activated protein kinase, as well as reduced fatty acid beta-oxidation.These findings indicate a potential relationship between renal proximal tubular epithelial cell CB1 receptor and the pathologic effects of obesity-induced renal lipotoxicity and nephropathy. In summary, the findings related to the CB1 receptor highlight its partial potential in acting as a therapeutic target for obesity-induced renal disease. Further studies are needed to ascertain the efficacy of modulating CB1 in the kidney to improve renal dysfunction independent of its effects on weight.The CB1 receptor has been shown to be upregulated in other renal disorders marked by interstitial inflammation and fibrosis, including acute interstitial nephritis.Using unilateral ureteral obstruction as an experimental model for renal fibrosis in mice, Lecru et al.showed that CB1 receptor expression was upregulated in UUO animals compared with controls. This is also associated with a marked increase in the renal content of 2-AG. Treatment of UUO mice with rimonabant reduced monocyte chemoattractant protein-1 synthesis and decreased macrophage infiltration.It was also shown that CB1 receptor activation led to enhanced VEGF levels, which subsequently reduced nephrin expression and protein levels.
There is accumulating evidence indicating the important role of CB1 and CB2 receptors and their modulation in the pathogenesis of various forms of AKI. With regard to ischemic AKI, selective CB1 and CB2 receptor agonists were found to have a dose-dependent effect in preventing tubular damage following renal ischemia/reperfusion injury in mouse kidney.In a separate study, however, the administration of cannabidiol, a non-psychoactive constituent of cannabis with poorly defined pharmacological properties, led to a reduction in renal tubular injury in rats following bilateral renal ischemia/reperfusion.Cannabidiol significantly attenuated the elevation of serum creatinine and renal malondialdehyde and nitric oxide levels associated with this condition.In a more recent study, a triazolopyrimidine-derived CB2 receptor agonist was demonstrated to play a protective role in in- flammatory renal injury following bilateral kidney ischemia/reperfusion.A series of studies have demonstrated the deleterious role of CB1 and the protective effects of CB2 activationon a nephrotoxic model of AKI in cisplatin-induced renal injury.Inhibiting CB1 receptor or activating CB2 receptor limited oxidative stress and inflammation and reduced tubular damage in kidneys of animals with cisplatin-induced AKI. In addition, ß-Caryophyllene, a natural agonist of CB2 receptor, dose-dependently protected against the deleterious effects of cisplatin-induced nephrotoxicity.Furthermore, CB1 and CB2 receptors have been shown to play a role in renal apoptotic and inflammatory signaling pathways.Indeed, activating CB1 receptors is known to result in enhanced expression of oxidative/nitrosative stress markers, which activate p38, MAPK, and c-Jun N-terminal kinase pathways, as well as nuclear factor kappa-light-chain-enhancer of activated B cells-dependent transcription of downstream proinflammatory target genes. Ultimately, the activation of either route leads to apoptotic cell death and inflammation in the kidney.
Conversely, CB2 receptor activation has been found to reduce proapoptotic signaling and mediate anti-inflammatory effects by attenuating immune cell infiltrates and inflammatory cytokine release.Mukhopadhyay et al.showed that a peripherally restricted CB2 receptor agonist , in a mouse model of cisplatin-induced nephrotoxicity, dosedependently attenuated renal dysfunction as measured by serum concentrations of blood urea nitrogen and creatinine. The protective effects of CB2 receptor activation in these studies were absent in CB2 receptor knockout mice, suggesting that CB2 receptors are a promising therapeutic target for reducing renal inflammation, oxidative/nitrosative stress, and apoptosis. Another major contributor to AKI, which is associated with significant morbidity and mortality, is sepsisassociated kidney injury .In a study using a cecal ligation and puncture mouse model of sepsis, CB2 receptor knockout mice demonstrated increased mortality, lung injury, bacteremia, neutrophil recruitment, and decreased p38 MAPK activity at the site of infection.Treatment with a selective CB2 receptor agonist reduced the effects caused by CLP, such as inflammation, lung damage, and neutrophil recruitment, and ultimately improved survival.These findings are in line with evidence demonstrating that following CB2 localization to leukocytes, their activation has been shown to mitigate leukocyte tumor necrosis factor-a-induced endothelial cell activation, adhesion and migration of leukocytes, as well as proinflammatory modulators. Therefore, CB2 receptor modulation may represent a novel therapeutic target in the treatment of SA-AKI.The mechanism by which the cannabinoid receptors modulate or recover tubular cell survival following acute damage are not well defined at this time. However, molecular differences in cannabinoid receptor mRNA and protein levels as well as differences in the physiological outcome of receptor activation are likely related to the type of AKI and to the abundance and localization of receptors. EC ligands in renal health and disease. While many of the studies evaluating the role of the EC system in renal homeostasis and pathophysiology focused on CB receptors and their modulation, it is important to keep in mind that the overall effects of activation and inhibition of the EC system are dependent on various factors,cannabis growing supplies only a portion of which is related to the activity of CB receptors. For example, the chief endogenous activators of the CB receptors, AEA and 2-AG, are present in substantial concentrations in the kidney; however, physiological responses elicited by these ligands under normal or pathological conditions have not been fully elucidated. Furthermore, detailed studies on how elevated or decreased levels of these ligands may impact renal function and pathology are scarce. For example, it is well known that AEA plays a role in the modulation of renal hemodynamics. Infusion of this ligand was found to be associated with vasorelaxation of juxtamedullary afferent arterioles in vitro, increased renal blood flow in rodents,and alteration of tubular sodium transport.While these effects may be partly mediated through the activation of CB1 and CB2 receptors, it is important to highlight that these findings indicate the total effect of this ligand and it is difficult to identify exactly which receptors are activated in each segment of the nephron. Furthermore, there are CB receptor–independent effects that are not accounted for when the role of these ligands were to be assessed only in the context of CB receptors. Recent studies have begun to address this important point by attempting to define the impact of these ligands in renal disease states.
Biernacki et al.described alterations to the EC system in primary and secondary HTN, noting that these conditions resulted in renal oxidative stress through increased reactive oxygen species and diminished levels of antioxidant enzymes. Despite the enhanced activity of FAAH and MGL in primary and secondary hypertensive rats, the levels of AEA and 2-AG in the kidney were significantly increased.Increasing endogenous levels of AEA by pharmacologically inhibiting its degradative enzyme,FAAH, with a selective FAAH inhibitor, URB597, was found to have resulted in the inhibition of ROS generation in both types of hypertensive rats. These effects were mediated through improvement in antioxidant defense in the primary spontaneously hypertensive rat kidney via the Nrf2 pathway, as well as through reduced proinflammatory responses in secondary hypertensive rats.Furthermore, URB597 augmented ROS-dependent phospholipid peroxidation products and levels of ECs in both types of hypertensive kidneys, which resulted in enhanced CB receptor expression in SHR rats and enhanced expression of CB2 and TRPV1 receptors in DOCA-salt rats.Chronic treatment of Wistar normotensive control rats with URB597 similarly enhanced phospholipid oxidation in the kidney, comparable to its administration in DOCA-salt rats.Thus, while the EC system appears to play a protective role in HTN, the administration of a FAAH inhibitor did not significantly alter the proinflammatory or oxidative conditions caused by primary HTN, and only created imbalances between ECs, oxidants, and proinflammatory factors in secondary HTN, potentially leading to the development of kidney dysfunction. With regard to other renal conditions, such as AKI, studies have shown varied responses to kidney injury in EC expression levels. Moradi et al.demonstrated that renal ischemia/reperfusion injury is associated with a significant increase in renal 2-AG content using a bilateral ischemia/reperfusion mouse model of AKI. It was found that the augmentation of kidney 2-AG concentrations following MGL inhibitor administration resulted in improved serum BUN, creatinine, and tubular damage score; however, the mRNA gene expression of renal inflammation and oxidative stress markers was not altered. Conversely, in a cisplatin-induced nephrotoxic model of AKI, cisplatin enhanced AEA but not 2- AG levels in renal tissue.To date, the mechanisms and conditions under which CB receptors are activated by ECs in the kidney—and subsequently the signaling cascades that result from this activation—have not been fully described. Studies have demonstrated conflicting results describing the role of AEA and CB1 receptor activation in mediating glomerular podocyte injury. Jourdan et al.showed that chronic exposure of human cultured podocytes to high glucose resulted in a significant upregulation in CB1 receptor gene expression, which is also associated with an increase in cellular AEA and 2-AG. This is associated with signs of inflammation and podocyte injury, which manifest as decreased podocin and nephrin and increased desmin gene expression.In contrast, Li et al.reported the protective functions of AEA following L-homocysteine -induced podocyte injury. AEA blocked Hcysinduced NLRP3 inflammasome activation in cultured podocytes and ameliorated podocyte dysfunction, ultimately precluding glomerular damage.Therefore, while the former study demonstrated that an increase in CB1 receptor gene expression accompanied by an upregulation in AEA and 2-AG is associated with podocyte injury, the latter study suggests that AEA exerts protective and anti-inflammatory effects in podocytes. Future studies are needed to investigate the role of EC ligands in CB receptor activation under varied conditions in renal health and disease.Inaccurate medication reconciliation is the source of many medication-related misadventures leading to hospital admissions and patient morbidity and mortality.In randomized controlled studies, pharmacist-led discharge medication reconciliation interventions result in hospital cost avoidance and improve patient safety.Valproic acid is an antiepileptic medication commonly used to treat seizures, bipolar disorder, and migraine headache.Its mechanism of action includes sodium channel inhibition, T-type calcium channel inhibition, suppression of glutamate, and inhibition of γ-aminobutyric acid metabolism. VPA is available in a variety of dosage forms, and peak plasma concentrations are achieved rapidly .With toxic ingestions, absorption and subsequent peak may be delayed; one case report reported peak serum levels 17 hours post ingestion.Therapeutic concentrations of VPA range from 50 to 100 µg/L, and it is 80–90% plasma protein bound.