Furthermore, studies using obese Zucker rats demon strated that the CB1 inverse agonist, rimonabant, ame liorated proteinuria in an animal model of obesity induced nephropathy.Treatment with rimonabant partially restored creatinine clearance, reduced glomeru losclerosis and tubular-interstitial fibrosis, 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 lipotoxic ity 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,vertical hydroponic system including acute interstitial nephritis.Using unilateral ureteral obstruction as an ex perimental model for renal fibrosis in mice, Lecru et al.showed that CB1 receptor expression was upre gulated in UUO animals compared with controls.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 in jury 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 inflammatory 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 inflamma tory 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 proinflam matory 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 me diate anti-inflammatory effects by attenuating immune cell infiltrates and inflammatory cytokine release.Mukhopadhyay et al. showed that a peripherally re stricted CB2 receptor agonist , in a mouse model of cisplatin-induced nephrotoxicity, dose dependently attenuated renal dysfunction as measured by serum concentrations of blood urea nitrogen and creatinine. The protective effects of CB2 receptor ac tivation in these studies were absent in CB2 receptor knockout mice, suggesting that CB2 receptors are a prom ising 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 sepsis associated 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 recruit ment, and decreased p38 MAPK activity at the site of in fection.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 recep tors 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 lo calization of receptors. 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, 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 vasorelax ation of juxtamedullary afferent arterioles in vitro,in creased 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 ox idative 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,cannabis grow set up the levels of AEA and 2-AG in the kidney were significantly in creased.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 gener ation 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 sec ondary 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 ex pression of CB2 and TRPV1 receptors in DOCA-salt rats.
Chronic treatment of Wistar normotensive con trol 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 proinflam matory 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 con centrations 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 nephro toxic 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 kid ney—and subsequently the signaling cascades that re sult from this activation—have not been fully described. Studies have demonstrated conflicting re sults describing the role of AEA and CB1 receptor acti vation in mediating glomerular podocyte injury. Jourdan et al.74 showed that chronic exposure of human cultured podocytes to high glucose resulted in a significant upregulation in CB1 receptor gene expres sion, which is also associated with an increase in cellu lar AEA and 2-AG. This is associated with signs of inflflammation 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 Hcys induced NLRP3 inflflammasome activation in cultured podocytes and ameliorated podocyte dysfunction, ulti mately 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 ex erts protective and anti-inflflammatory effects in podo cytes. Future studies are needed to investigate the role of EC ligands in CB receptor activation under varied conditions in renal health and disease.Among US adults in 2019, e-cigarettes were the most commonly used non-cigarette tobacco product , with use of e-cigarettes highest among adults aged 18–24 years . The convenience of newer pod like devices, the use of nicotine salts to provide higher doses of nico tine with less throat irritation , and marketing of e-cigarettes as smoking cessation aids all contribute to lower perceived harm and may account for recent increases in use among adults . Over a third of adult e-cigarette users also self-identify as current users of tobacco cigarettes , and the most common reasons given for e cigarette use are for cessation of tobacco cigarettes or health-related concerns . While smokers may use e-cigarettes to reduce their exposure to the toxic chemicals found in tobacco cigarettes , there is insufficient evidence to conclude that e-cigarettes are effective smoking cessation aids . Little is known about e-cigarette use among vulnerable populations such as those with SUDs. Among SUD treatment clients high rates of current ciga rette smoking have been reported, however, with lower rates of past 30-day e cigarette use. Similar to the general population, the majority of current e-cigarette users receiving care in SUD treatment programs are also current users of tobacco cigarettes , and many report that they use e-cigarettes to either quit or reduce cigarette smoking . These findings highlight the importance of considering cigarette smoking status to understand e cigarette use among clients in SUD treatment to inform the development of anti-vaping messages to support smoking cessation in this population. Although the studies by Gubner et al. and Baldassarri et al. examined the correlates of current e-cigarette use among patients in SUD treatment, these studies did not focus on beliefs and attitudes for using e-cigarettes as a smoking cessation aid.