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Current treatments include renin\u2010angiotensin\u2010aldosterone system (RAAS) blockers and sodium\u2010glucose co\u2010transporter 2 (SGLT2) inhibitors. The cannabinoid CB\n                      <jats:sub>1<\/jats:sub>\n                      receptor is a potential therapeutic target. We explored combining CB\n                      <jats:sub>1<\/jats:sub>\n                      receptor inverse agonism and SGLT2 inhibition for treating DN, to offer better reno\u2010protection.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental approach<\/jats:title>\n                    <jats:p>\n                      C57BLKS\u2010Lepr\n                      <jats:sup>db\/db<\/jats:sup>\n                      and control mice were fed a high\u2010protein diet for 9\u2009weeks. After 5\u2009weeks, db\/db mice were either exposed to placebo, empagliflozin (SGLT2 inhibitor), monlunabant (CB\n                      <jats:sub>1<\/jats:sub>\n                      receptor inverse agonist) or a combination of both compounds (same dose) by daily oral gavage for 28\u2009days. Diagnostic parameters for DN were analysed, along with markers of oxidative stress, inflammation and renal fibrosis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key results<\/jats:title>\n                    <jats:p>\n                      Both single treatments improved albuminuria and albumin\u2010to\u2010creatinine 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\u2010treated 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\n                      <jats:sub>1<\/jats:sub>\n                      receptors and SGLT2, respectively.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and implications<\/jats:title>\n                    <jats:p>\n                      Taken together, these data strongly suggest that a poly\u2010pharmacological approach combining both SGLT2 inhibitors and CB\n                      <jats:sub>1<\/jats:sub>\n                      receptor inverse agonism represents a promising therapeutic strategy for managing DN, with better reno\u2010protection than mono\u2010therapies.\n                    <\/jats:p>\n                  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