Inhibition of sodium-glucose cotransporter 2 suppresses renal stone formation
Inhibition of sodium-glucose cotransporter 2 suppresses renal stone formation
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DOI：
10.1016/j.phrs.2022.106524
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发表时间：
2022-11-05
影响因子：
9.3
通讯作者：
Mori, Takefumi
中科院分区：
文献类型：
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作者：
Anan, Go;Hirose, Takuo;Mori, Takefumi
背景与目的：肾结石是一种常见的肾脏疾病，目前尚无有效的药物治疗。钠-葡萄糖协同转运蛋白 2 (SGLT2) 抑制剂是一种抗糖尿病药物，具有利尿和抗炎特性，可以预防肾结石。在这里，我们利用大规模流行病学数据、动物模型和细胞培养实验研究了 SGLT2 抑制治疗肾结石的潜力。 方法：本研究纳入了日本管理数据库中可用的糖尿病患者数据（n = 1,538,198），并根据 SGLT2 抑制剂处方状态对它们进行分类。在动物实验中，用乙二醇诱导 Sprague-Dawley 大鼠肾草酸钙结石，并使用 SGLT1/2 抑制剂根皮苷进行治疗。在 SGLT2 缺陷小鼠和人类近端肾小管细胞系 HK-2 中评估了 SGLT2 特异性抑制对肾结石形成的影响。 结果：SGLT2 抑制剂处方组的糖尿病男性肾结石患病率显着低于非 SGLT2 抑制剂处方组。根皮苷可减轻大鼠肾结石形成并下调肾损伤分子 1 (Kim1) 和骨桥蛋白 (Opn) 的表达，而饮水量和尿量不变。它抑制炎症和巨噬细胞标志物表达，表明 SGLT2 抑制剂在减轻炎症方面的作用。 SGLT2 缺陷小鼠对乙醛酸诱导的草酸钙结石形成有抵抗力，同时 Opn 表达减少和肾损伤。 HK-2 细胞中 SGLT2 沉默后，高糖诱导的 OPN 和 CD44 上调以及草酸钙的细胞表面粘附减少。结论：总的来说，我们的研究结果表明，SGLT2 抑制可预防肾结石形成，可能是一种有前景的肾结石治疗方法。
Background and aims: Nephrolithiasis is a common renal disease with no effective medication. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, an anti-diabetic agent, have diuretic and anti-inflammatory properties and could prevent nephrolithiasis. Here, we investigated the potential of SGLT2 inhibition against nephrolithiasis using large-scale epidemiological data, animal models, and cell culture experiments.Methods: This study included the data of diabetic patients (n = 1,538,198) available in the Japanese administrative database and divided them according to SGLT2 inhibitor prescription status. For animal experiments, renal calcium oxalate stones were induced by ethylene glycol in Sprague-Dawley rats, and phlorizin, an SGLT1/2 inhibitor, was used for the treatment. The effects of SGLT2-specific inhibition for renal stone formation were assessed in SGLT2-deficient mice and a human proximal tubular cell line, HK-2.Results: Nephrolithiasis prevalence in diabetic men was significantly lower in the SGLT2 inhibitor prescription group than in the non-SGLT2 inhibitor prescription group. Phlorizin attenuated renal stone formation and downregulated the kidney injury molecule 1 (Kim1) and osteopontin (Opn) expression in rats, with unchanged water intake and urine volume. It suppressed inflammation and macrophage marker expression, suggesting the role of the SGLT2 inhibitor in reducing inflammation. SGLT2-deficient mice were resistant to glyoxylic acid-induced calcium oxalate stone formation with reduced Opn expression and renal damages. High glucose-induced upregulation of OPN and CD44 and cell surface adhesion of calcium oxalate reduced upon SGLT2-silencing in HK-2 cells.Conclusion: Overall, our findings identified that SGLT2 inhibition prevents renal stone formation and may be a promising therapeutic approach against nephrolithiasis.