Blockade of cannabinoid CB₁ receptors potentiates the anti‐fibrotic effects mediated by SGLT2 inhibition in a mouse model of diabetic nephropathy

Background and purpose Diabetic nephropathy (DN) is a common complication of diabetes. Current treatments include renin‐angiotensin‐aldosterone system (RAAS) blockers and sodium‐glucose co‐transporter 2 (SGLT2) inhibitors. The cannabinoid CB 1 receptor is a potential therapeutic target. We explored combining CB 1 receptor inverse agonism and SGLT2 inhibition for treating DN, to offer better reno‐protection. Experimental approach C57BLKS‐Lepr db/db and control mice were fed a high‐protein diet for 9 weeks. After 5 weeks, db/db mice were either exposed to placebo, empagliflozin (SGLT2 inhibitor), monlunabant (CB 1 receptor inverse agonist) or a combination of both compounds (same dose) by daily oral gavage for 28 days. Diagnostic parameters for DN were analysed, along with markers of oxidative stress, inflammation and renal fibrosis. Key results Both single treatments improved albuminuria and albumin‐to‐creatinine ratios, but the combination was more effective. Similar results were seen for inflammatory oxidative stress markers. The combination showed additive protective effects on glomerular morphology, podocyte loss and proximal tubular cell injury. Dual treatment significantly reduced tubulointerstitial fibrosis compared to monotherapy and vehicle‐treated mice. Transcriptomic analysis identified the STAT3 signalling pathway as a key mediator, with decreased STAT3 phosphorylation observed with both treatments. Key mediators involved included angiopoietin 1 and fibroblast growth factor 20, which modulated the STAT3 pathway via CB 1 receptors and SGLT2, respectively. Conclusions and implications Taken together, these data strongly suggest that a poly‐pharmacological approach combining both SGLT2 inhibitors and CB 1 receptor inverse agonism represents a promising therapeutic strategy for managing DN, with better reno‐protection than mono‐therapies.