Sitagliptin ameliorates oxidative stress in experimental diabetic nephropathy by diminishing the miR-200a/Keap-1/Nrf2 antioxidant pathway.
Sitagliptin ameliorates oxidative stress in experimental diabetic nephropathy by diminishing the miR-200a/Keap-1/Nrf2 antioxidant pathway.
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DOI：
10.2147/dmso.s132537
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Mas S
中科院分区：
文献类型：
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作者：
Civantos E;Bosch E;Ramirez E;Zhenyukh O;Egido J;Lorenzo O;Mas S
西格列汀是一种用于2型糖尿病治疗的二肽基肽酶-4 （DPP-4）抑制剂，已被证明对糖尿病慢性肾脏疾病具有保护作用，部分原因是其多效性作用。然而，其对肾脏的潜在直接影响仍未完全确定。通过蛋白质组学和miRNA分析，我们进一步揭示了西格列汀在氧化应激中的作用及其潜在机制。9月龄野生型（Wistar）、II型糖尿病Goto-Kakizaki （GK）和西格列汀治疗的GK大鼠（GK+Sita）（每天10 mg kg−1）的肾皮质样本进行了定量miRNA转录组阵列、免疫组织化学和Western blot研究。肾GK和GK+Sita样品也用凝胶电泳进行分析。使用生物信息学工具来发现改变蛋白与相关miRNA表达之间的关系。研究还在培养的小管细胞中进行，以证实体内数据。糖尿病大鼠GK表现为蛋白尿、肾间质炎症浸润和纤维化，西格列汀治疗20周后改善。糖尿病大鼠GK和Wistar的蛋白质组学分析显示，39个主要与氧化应激和分解代谢相关的蛋白质表达差异。此外，GK大鼠的15个mirna也发生了显著改变。西格列汀治疗与糖尿病肾脏抗氧化反应的调节有关，涉及miR-200a（一种新型Keap-1抑制剂）和miR-21的下调，与临床和形态学改善相一致。这些数据进一步支持了DPP-4抑制剂可在糖尿病肾病患者中发挥直接肾保护作用的概念。
Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor used in type 2 diabetes therapy, has demonstrated protective effects in diabetic chronic kidney disease, in part due to its pleiotropic actions. However, its potential direct effects on the kidney are still not completely defined. Here, by means of proteomics and miRNA profiling, we have further unveiled the role of sitagliptin in oxidative stress, as well as the underlying mechanisms. Renal cortex samples from 9-month-old wild-type (Wistar), type II diabetic Goto-Kakizaki (GK) and sitagliptin-treated GK rats (GK+Sita) (10 mg kg−1 per day) were subjected to quantitative miRNA transcriptomic array, immunohistochemistry and Western blot studies. Renal GK and GK+Sita samples were also analyzed by differential in-gel electrophoresis. Bioinformatic tools were used to find out the relationships between altered proteins and related miRNA expression. Studies were also carried out in cultured tubular cells to confirm in vivo data. Diabetic GK rats exhibited proteinuria, renal interstitial inflammatory infiltrates and fibrosis, which improved by 20 weeks of sitagliptin treatment. Proteomic analysis of diabetic GK and Wistar rats showed a differential expression of 39 proteins mostly related to oxidative stress and catabolism. In addition, 15 miRNAs were also significantly altered in GK rats. Treatment with sitagliptin was associated with modulation of antioxidant response in the diabetic kidney, involving a downregulation of miR-200a, a novel Keap-1 inhibitor and miR-21, coincidentally with the clinical and the morphological improvement. These data further support the concept that DPP-4 inhibitors could exert a direct reno-protective effect in patients with diabetic nephropathy.