Cannabinoid receptor 2 (CB) agonists and l-arginine ameliorate diabetic nephropathy in rats by suppressing inflammation and fibrosis through NF-κβ pathway

Diabetic nephropathy (DN) is a condition that leads to end-stage chronic kidney disease characterized by inflammation and a deficiency of nitric oxide (NO). Cannabinoid receptor (CB) activation by specific agonist reduces nuclear factor kappa beta (NF-κβ) expression. Beta caryophyllene (BCP), a natural CB receptor activator, protects kidney function in several diseases. l-Arginine (LA) modulates several physiological processes by donating nitric oxide (NO). Hence, we tested a novel BCP-LA combination to treat DN and investigated its molecular mechanisms. BCP, LA, and combinations of both were evaluated in LPS-induced RAW 264.7 macrophage inflammation as well as in streptozotocin (55 mg/kg)-induced diabetes in SD rats. Diabetic rats were administered 200 mg/kg of BCP, 100 mg/kg of LA, and combination of both orally for 28 days. Biochemical markers and inflammatory cytokines were assessed in plasma; also, kidney tissue was examined for renal oxidative stress injury, NF-κβ expression, and histology. After 28 days of treatment, BCP and LA combination significantly lowered plasma glucose levels than the disease control group. BCP and LA also normalized renal markers and oxidative stress of diabetic rats. Plasma and RAW macrophage cell lines showed reduced levels of IL-6 and TNF-α (P < 0.001). Histopathological evaluations revealed that BCP and LA together decreased renal fibrosis and collagen deposition also improved nephrotic indices. Meanwhile, the effect of BCP and LA together significantly reduced the NF-κβ (P < 0.01) against diabetic rats. These results indicate that the innovative regimen BCP with LA may be a therapeutic treatment for DN, as it protects kidney tissue from diabetes via NF-κβ inhibition. Graphical abstract: [Figure not available: see fulltext.]