Matsui Sho, Yamamoto Takeshi, Takabatake Yoshitsugu, Takahashi Atsushi, Namba-Hamano Tomoko, Matsuda Jun, Minami Satoshi, Sakai Shinsuke, Yonishi Hiroaki, Nakamura Jun, Maeda Shihomi, Matsumoto Ayumi, Matsui Isao, Yanagita Motoko, Isaka Yoshitaka
Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan.
Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Autophagy. 2025 Mar;21(3):583-597. doi: 10.1080/15548627.2024.2410621. Epub 2024 Oct 14.
The renoprotective effects of SLC5A2/SGLT2 (solute carrier 5 (sodium/glucose cotransporter), member 2) inhibitors have recently been demonstrated in non-diabetic chronic kidney disease (CKD), even without overt albuminuria. However, the mechanism underlying this renoprotection is largely unclear. We investigated the renoprotective mechanisms of the SLC5A2 inhibitor empagliflozin with a focus on ALB (albumin) reabsorption and macroautophagy/autophagy in proximal tubules using wild-type or drug-inducible or knockout mice with high-fat diet (HFD)-induced obesity or 5/6 nephrectomy that elevated intraglomerular pressure without overt albuminuria. Empagliflozin treatment of HFD-fed mice reduced several hallmarks of lipotoxicity in the proximal tubules, such as phospholipid accumulation in the lysosome, inflammation and fibrosis. Empagliflozin, which decreases intraglomerular pressure, not only reduced the HFD-induced increase in ALB reabsorption LRP2 in the proximal tubules (. total nephron ALB filtration), as assessed by urinary ALB excretion caused by genetic ablation of , but also ameliorated the HFD-induced imbalance in circulating ALB-bound fatty acids. Empagliflozin alleviated the HFD-induced increase in autophagic demand and successfully prevented autophagic stagnation in the proximal tubules. Similarly, empagliflozin decreased ALB exposure and autophagic demand in 5/6 nephrectomized mice. Finally, empagliflozin reduced HFD-induced vulnerability to ischemia-reperfusion injury, whereas LRP2 blockade and ablation separately diminished this effect. Our findings indicate that empagliflozin reduces ALB exposure and prevents autophagic stagnation in the proximal tubules even without overt albuminuria. Autophagy improvement may be critical for the renoprotection mediated by SLC5A2 inhibition.
溶质载体5（钠/葡萄糖共转运体）成员2（SLC5A2/SGLT2）抑制剂的肾脏保护作用最近在非糖尿病慢性肾脏病（CKD）中得到证实，即使没有明显蛋白尿。然而，这种肾脏保护作用的潜在机制在很大程度上尚不清楚。我们使用野生型、药物诱导型或基因敲除小鼠，这些小鼠通过高脂饮食（HFD）诱导肥胖或进行5/6肾切除以升高肾小球内压力但无明显蛋白尿，研究了SLC5A2抑制剂恩格列净的肾脏保护机制，重点关注近端小管中的白蛋白（ALB）重吸收和巨自噬/自噬。恩格列净治疗高脂饮食喂养的小鼠可减少近端小管中脂毒性的几个特征，如溶酶体中的磷脂积累、炎症和纤维化。恩格列净可降低肾小球内压力，不仅减少了高脂饮食诱导的近端小管中ALB重吸收增加（通过基因敲除导致的尿ALB排泄评估，占总肾单位ALB滤过的比例），还改善了高脂饮食诱导的循环中ALB结合脂肪酸的失衡。恩格列净减轻了高脂饮食诱导的自噬需求增加，并成功预防了近端小管中的自噬停滞。同样，恩格列净降低了5/6肾切除小鼠的ALB暴露和自噬需求。最后，恩格列净降低了高脂饮食诱导的对缺血-再灌注损伤的易感性，而单独阻断LRP2和基因敲除分别减弱了这种作用。我们的研究结果表明，即使没有明显蛋白尿，恩格列净也能减少ALB暴露并预防近端小管中的自噬停滞。自噬改善可能是SLC5A2抑制介导的肾脏保护的关键。
