Background

Diabetic kidney disease (DKD) is a secondary complication of diabetes mellitus and a leading cause of chronic kidney disease.

Aim

To investigate the impact of long-term canagliflozin treatment on DKD and elucidate its underlying mechanism.

Methods

DKD model was established using high-fat diet and streptozotocin in male C57BL/6J mice (n = 30). Mice were divided into five groups and treated for 12 weeks. 1) normal control mice, 2) DKD model, 3) mice treated low-dose of canagliflozin, 4) high-dose of canagliflozin and 5) β-hydroxybutyrate. Mice kidney morphology and function were evaluated, and a metabolomics analysis was performed.

Results

Canagliflozin treatment reduced blood creatinine and urine nitrogen levels and improved systemic insulin sensitivity and glucose tolerance in diabetic mice. Additionally, a decrease in histological lesions including collagen and lipid deposition in the kidneys was observed. β-hydroxybutyrate treatment did not yield a comparable outcome. The metabolomics analysis revealed that canagliflozin induced alterations in amino acid metabolism profiles in the renal tissue of diabetic mice.

Conclusion

Canagliflozin protects the kidneys of diabetic mice by increasing the levels of essential amino acids, promoting mitochondrial homeostasis, mitigating oxidative stress, and stimulating the amino acid-dependent tricarboxylic acid cycle.

中文翻译：

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SGLT2抑制剂通过调节糖尿病肾病小鼠的肾代谢来改善肾功能和形态

背景

糖尿病肾病（DKD）是糖尿病的继发并发症，也是慢性肾病的主要原因。

目的

探讨长期卡格列净治疗对 DKD 的影响并阐明其潜在机制。

方法

采用高脂饮食和链脲佐菌素对雄性 C57BL/6J 小鼠（n  = 30）建立 DKD 模型。将小鼠分为 5 组并治疗 12 周。1）正常对照小鼠，2）DKD模型，3）低剂量卡格列净治疗的小鼠，4）高剂量卡格列净和5）β-羟基丁酸盐。评估小鼠肾脏形态和功能，并进行代谢组学分析。

结果

卡格列净治疗降低了糖尿病小鼠的血肌酐和尿氮水平，并改善了全身胰岛素敏感性和葡萄糖耐量。此外，观察到组织学病变减少，包括肾脏中的胶原蛋白和脂质沉积。β-羟基丁酸治疗没有产生可比较的结果。代谢组学分析表明，卡格列净诱导糖尿病小鼠肾组织氨基酸代谢谱的改变。

结论

Canagliflozin 通过增加必需氨基酸水平、促进线粒体稳态、减轻氧化应激和刺激氨基酸依赖性三羧酸循环来保护糖尿病小鼠的肾脏。