CBGA ameliorates inflammation and fibrosis in nephropathy

Abstract

Cannabidiol (CBD) is thought to have multiple biological effects, including the ability to attenuate inflammatory processes. Cannabigerols (CBGA and its decarboxylated CBG molecule) have pharmacological profiles similar to CBD. The endocannabinoid system has recently emerged to contribute to kidney disease, however, the therapeutic properties of cannabinoids in kidney disease remain largely unknown. In this study, we determined whether CBD and CBGA can attenuate kidney damage in an acute kidney disease model induced by the chemotherapeutic cisplatin. In addition, we evaluated the anti-fibrosis effects of these cannabinoids in a chronic kidney disease model induced by unilateral ureteral obstruction (UUO). We find that CBGA, but not CBD, protects the kidney from cisplatin-induced nephrotoxicity. CBGA also strongly suppressed mRNA of inflammatory cytokines in cisplatin-induced nephropathy, whereas CBD treatment was only partially effective. Furthermore, both CBGA and CBD treatment significantly reduced apoptosis through inhibition of caspase-3 activity. In UUO kidneys, both CBGA and CBD strongly reduced renal fibrosis. Finally, we find that CBGA, but not CBD, has a potent inhibitory effect on the channel-kinase TRPM7. We conclude that CBGA and CBD possess reno-protective properties, with CBGA having a higher efficacy, likely due to its dual anti-inflammatory and anti-fibrotic effects paired with TRPM7 inhibition.

Exploring the Role of the Endocannabinoid System in Chronic Kidney Disease: Implications for Therapeutic Interventions

“…Cannabinoids operate through diverse mechanisms, impacting various biological targets, including G protein-coupled receptors, notably CB1 and CB2 receptors, as well as 5-HT1A and 5-HT2A serotonin receptors. Additionally, cannabinoids influence various ion channels, such as TRPV1, TRPV2, TRPV3, TRPV4, TRPA1, and TRPM8 REIN et al, [16] SUZUKI; FLEIG; PENNER, [7] BARUTTA et al, [4].…”

“…The acidic form of CBG (CBGA) is noted for its neuroprotective properties; however, further elucidation is required to understand its properties and pharmacological effects fully. According to Suzuki, Fleig, and Penner [7] CBGA stands out as the most potent cannabinoid inhibitor of store-operated calcium entry and IL-2 production in T cells. This characteristic positions it as a promising candidate molecule for modulating calcium signaling and inflammatory mechanisms in various pro-inflammatory immune cells, potentially influencing kidney inflammation.…”

“…The endocannabinoid system (ECS) constitutes a significant signaling pathway wherein lipid ligands, referred to as cannabinoids, bind to cannabinoid receptors, which also encompass endocannabinoid metabolic enzymes ARCERI et al, [2,6]. This system contributes to various cellular processes, with its components playing crucial roles in a range of physiological and pathological processes, including but not limited to energy metabolism and inflammation (PERMYAKOVA et al, 2023; SUZUKI; FLEIG; PENNER, [7] ZHOU et al, [8] The ECS signaling pathway comprises two principal receptors, namely the cannabinoid receptor type 1 (CB1) and the cannabinoid receptor type 2 (CB2). Specifically, this pathway involves endogenous cannabinoid ligands, commonly referred to as endocannabinoids (ARCERI et al, [2].…”

“…Kidney diseases are instigated and perpetuated through an intricate interplay of various mechanisms, encompassing inflammation, oxidative stress, epithelial-mesenchymal transition, cytokine activation, growth factors, and genetic factors. Profound comprehension of these implicated mechanisms is imperative for the formulation of efficacious treatments for renal diseases [7]. Furthermore, recent data have demonstrated that alterations in the ECS and subsequent pathways may contribute to the pathogenesis of kidney diseases, both acute and chronic [10,4].…”

Transient Receptor Potential Melastatin 7 (TRPM7) Ion Channel Inhibitors: Preliminary SAR and Conformational Studies of Xenicane Diterpenoids from the Hawaiian Soft Coral Sarcothelia edmondsoni

“…Systemic treatment of mice with CBGA ameliorates chronic kidney disease induced by ureteral obstruction and inhibits cisplatin-induced nephrotoxicity. This is likely due to CBGA’s dual anti-inflammatory and anti-fibrotic activity paired with TRPM7 inhibition. , FTY720 is a clinically useful treatment for multiple sclerosis that, once phosphorylated, inhibits sphingosine 1-phosphate signaling, but also inhibits TRPM7 in its nonphosphorylated form with an IC 50 of 720 nM . Recently, Chubanov and colleagues identified several compounds that are also able to differentiate between TRPM7 and its sister channel TRPM6 .…”