The sodium–glucose cotransporter 2 inhibitor tofogliflozin prevents diabetic kidney disease progression in type 2 diabetic mice,FEBS Open Bio

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The sodium–glucose cotransporter 2 inhibitor tofogliflozin prevents diabetic kidney disease progression in type 2 diabetic mice
FEBS Open Bio ( IF 2.8 ) Pub Date : 2020-10-24 , DOI: 10.1002/2211-5463.13014
Zi Li ₁ , Maki Murakoshi ₁ , Saki Ichikawa ₁ , Takeo Koshida ₁ , Eri Adachi ₁ , Chigure Suzuki ₂ , Seiji Ueda ₁ , Tomohito Gohda ₁ , Yusuke Suzuki ₁

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Trials on cardiovascular and renal outcomes in patients with type 2 diabetes have consistently demonstrated that sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of diabetic kidney disease (DKD) progression. However, their renal protective mechanisms have yet to be completely understood and the effect on albuminuria reduction in animal models is controversial. We investigated these issues using KK and KK‐A^y mice as a control (CTRL) and as a model for type 2 diabetes (DKD), respectively. KK‐A^y mice were treated with 0.015% tofogliflozin, which is an SGLT2 inhibitor, starting at seven weeks of age for eight weeks. Compared with the CTRL mice, the DKD mice had higher HbA1c levels and albuminuria. Although tofogliflozin treatment significantly lowered HbA1c levels, it did not reverse albuminuria. Tofogliflozin treatment enhanced damage in both the glomerular (i.e., enlarged mesangial area, increased foot process effacement rate, and decreased number of WT‐1‐positive cells) and tubulointerstitial (increased protein levels of KIM‐1 and MCP‐1, increased number of macrophages, and abnormal mitochondrial morphology) areas. Our results suggest that tofogliflozin may prevent glomerular and tubulointerstitial damage, partly by ameliorating hyperglycemia, renal inflammation, and abnormal mitochondrial morphology.

中文翻译：

钠-葡萄糖协同转运蛋白 2 抑制剂 tofogliflozin 可预防 2 型糖尿病小鼠的糖尿病肾病进展

对 2 型糖尿病患者的心血管和肾脏结局的试验一致表明，钠-葡萄糖协同转运蛋白 2 (SGLT2) 抑制剂可降低糖尿病肾病 (DKD) 进展的风险。然而，它们的肾脏保护机制尚未完全了解，并且在动物模型中对蛋白尿减少的影响存在争议。我们分别使用 KK 和 KK- A ^y小鼠作为对照 (CTRL) 和 2 型糖尿病 (DKD) 模型研究了这些问题。KK- A ^y从 7 周龄开始，小鼠接受 0.015% tofogliflozin（一种 SGLT2 抑制剂）治疗，持续 8 周。与 CTRL 小鼠相比，DKD 小鼠具有更高的 HbA1c 水平和白蛋白尿。尽管托福格列净治疗显着降低了 HbA1c 水平，但并没有逆转白蛋白尿。Tofogliflozin 治疗增强了肾小球（即扩大的系膜区域，增加足突消失率，减少 WT-1 阳性细胞数量）和肾小管间质（增加 KIM-1 和 MCP-1 蛋白水平，增加数量巨噬细胞和异常线粒体形态）区域。我们的结果表明 tofogliflozin 可以预防肾小球和肾小管间质损伤，部分是通过改善高血糖、肾脏炎症和异常线粒体形态。

更新日期：2020-12-03

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