Pointeau Océane, Ba Awa Isma, Geissler Audrey, Barbosa Romain, Basu Abhishek, Muhammad Arif, Nivot Marina, Loriot Maéva, Leemput Julia, Passilly-Degrace Patricia, Causse Sébastien, Demizieux Laurent, François Hélène, Vergès Bruno, Duan Jianmin, Gaucher Geneviève, Harvey Michael, Degrace Pascal, Crater Glenn, Cinar Resat, Jourdan Tony
Université Bourgogne Europe, INSERM, Center for Translation and Molecular medicine (CTM), Team PAthophysiology of DYSlipidemia (PADYS), Dijon, France.
Université Bourgogne Europe, INSERM, ImaFlow Corefacility, US58 BioSanD, Dijon, France.
Br J Pharmacol. 2025 Nov;182(21):5355-5377. doi: 10.1111/bph.70118. Epub 2025 Jul 11.
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 receptor is a potential therapeutic target. We explored combining CB receptor inverse agonism and SGLT2 inhibition for treating DN, to offer better reno-protection.
C57BLKS-Lepr 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 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.
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 receptors and SGLT2, respectively.
Taken together, these data strongly suggest that a poly-pharmacological approach combining both SGLT2 inhibitors and CB receptor inverse agonism represents a promising therapeutic strategy for managing DN, with better reno-protection than mono-therapies.
糖尿病肾病（DN）是糖尿病常见的并发症。目前的治疗方法包括肾素 - 血管紧张素 - 醛固酮系统（RAAS）阻滞剂和钠 - 葡萄糖协同转运蛋白2（SGLT2）抑制剂。大麻素CB受体是一个潜在的治疗靶点。我们探索将CB受体反向激动作用与SGLT2抑制相结合用于治疗DN，以提供更好的肾脏保护。
给C57BLKS - Lepr小鼠和对照小鼠喂食高蛋白饮食9周。5周后，通过每日口服灌胃给予db/db小鼠安慰剂、恩格列净（SGLT2抑制剂）、莫伦班特（CB受体反向激动剂）或两种化合物的组合（相同剂量），持续28天。分析DN的诊断参数以及氧化应激、炎症和肾纤维化的标志物。
两种单一治疗均改善了蛋白尿和白蛋白与肌酐比值，但联合治疗更有效。炎症氧化应激标志物也有类似结果。联合治疗对肾小球形态、足细胞丢失和近端肾小管细胞损伤显示出相加的保护作用。与单一疗法和载体处理的小鼠相比，双重治疗显著降低了肾小管间质纤维化。转录组分析确定STAT3信号通路是关键介质，两种治疗均观察到STAT3磷酸化降低。涉及的关键介质包括血管生成素1和成纤维细胞生长因子20，它们分别通过CB受体和SGLT2调节STAT3通路。
综上所述，这些数据强烈表明，将SGLT2抑制剂和CB受体反向激动作用相结合的多药联合方法是一种有前景的治疗DN的策略，比单一疗法具有更好的肾脏保护作用。
