Comprehensive renoprotective effects of ipragliflozin on early diabetic nephropathy in mice
Comprehensive renoprotective effects of ipragliflozin on early diabetic nephropathy in mice
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DOI：
10.1038/s41598-018-22229-5
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发表时间：
2018-03-05
影响因子：
4.6
通讯作者：
Tamagaki, Keiichi
中科院分区：
文献类型：
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作者：
Kamezaki, Michitsugu;Kusaba, Tetsuro;Tamagaki, Keiichi
临床和实验研究表明，葡萄糖共转运蛋白2抑制剂(SGLT2i)有助于预防糖尿病肾病的进展。为了阐明SGLT2i在糖尿病肾病发生发展的分子机制上的药理作用，我们给2型糖尿病小鼠注射了不同剂量的SGLT2i，伊普洛秦。大剂量伊帕格列齐治疗8周，可降低血糖水平，减少尿白蛋白排泄。高剂量和低剂量伊帕格列齐均可抑制肾脏和肾小球肥大，并减少NADPH氧化酶4的表达和随后的氧化应激。使用肾小球分离对肾小球表型的分析表明，伊帕格列星保留了足细胞的完整性，并减少了氧化应激。在肾组织缺氧方面，短期伊帕格列齐治疗改善了肾皮质的氧分压，SGLT2在肾皮质中主要表达。然后，我们给1型糖尿病小鼠服用伊帕格列齐，发现高剂量和低剂量的伊帕格列津都减少了尿白蛋白的排泄。综上所述，我们在体内证实了伊帕格列齐对早期糖尿病肾病的作用存在剂量依赖性差异。在早期糖尿病肾病中，即使是小剂量的伊帕格列星也能减少肾皮质缺氧和血流动力学异常。除了这些作用外，大剂量伊帕格列齐还通过减少肾小管上皮细胞和肾小球足细胞的氧化应激而发挥肾脏保护作用。
Clinical and experimental studies have shown that sodium glucose co-transporter 2 inhibitors (SGLT2i) contribute to the prevention of diabetic kidney disease progression. In order to clarify its pharmacological effects on the molecular mechanisms underlying the development of diabetic kidney disease, we administered different doses of the SGLT2i, ipragliflozin, to type 2 diabetic mice. A high-dose ipragliflozin treatment for 8 weeks lowered blood glucose levels and reduced urinary albumin excretion. High-and low-dose ipragliflozin both inhibited renal and glomerular hypertrophy, and reduced NADPH oxidase 4 expression and subsequent oxidative stress. Analysis of glomerular phenotypes using glomeruli isolation demonstrated that ipragliflozin preserved podocyte integrity and reduced oxidative stress. Regarding renal tissue hypoxia, a short-term ipragliflozin treatment improved oxygen tension in the kidney cortex, in which SGLT2 is predominantly expressed. We then administered ipragliflozin to type 1 diabetic mice and found that high-and low-dose ipragliflozin both reduced urinary albumin excretion. In conclusion, we confirmed dose-dependent differences in the effects of ipragliflozin on early diabetic nephropathy in vivo. Even low-dose ipragliflozin reduced renal cortical hypoxia and abnormal hemodynamics in early diabetic nephropathy. In addition to these effects, highdose ipragliflozin exerted renoprotective effects by reducing oxidative stress in tubular epithelia and glomerular podocytes.