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Linagliptin affects IRS1/Akt signaling and prevents high glucose-induced apoptosis in podocytes.
Scientific Reports ( IF 4.6 ) Pub Date : 2020-04-01 , DOI: 10.1038/s41598-020-62579-7
Akira Mima 1 , Toshinori Yasuzawa 2, 3 , Tomomi Nakamura 3 , Shigeru Ueshima 3, 4, 5
Affiliation  

Diabetes-induced podocyte apoptosis is considered to play a critical role in the pathogenesis of diabetic kidney disease (DKD). We proposed that hyperglycaemia can induce podocyte apoptosis by inhibiting the action of podocyte survival factors, thus inactivating the cellular effects of insulin signalling. In this study, we aimed to determine the effects of linagliptin on high glucose-induced podocyte apoptosis. Linagliptin reduced the increase in DNA fragmentation as well as the increase in TUNEL-positive cells in podocytes induced by high-glucose condition. Furthermore, linagliptin improved insulin-induced phosphorylation of insulin receptor substrate 1 (IRS1) and Akt, which was inhibited in high-glucose conditions. Adenoviral vector-mediated IRS1 overexpression in podocytes partially normalised DNA fragmentation in high-glucose conditions, while downregulation of IRS1 expression using small interfering RNA increased DNA fragmentation even in low-glucose conditions. Because reactive oxygen species inhibit glomerular insulin signalling in diabetes and Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is one of the most important intrinsic antioxidative systems, we evaluated whether linagliptin increased Nrf2 in podocytes. High-glucose condition and linagliptin addition increased Nrf2 levels compared to low-glucose conditions. In summary, linagliptin offers protection against DKD by enhancing IRS1/Akt insulin signalling in podocytes and partially via the Keap1/Nrf2 pathway. Our findings suggest that linagliptin may induce protective effects in patients with DKD, and increasing IRS1 levels could be a potential therapeutic target in DKD.



中文翻译:

利格列汀可影响IRS1 / Akt信号传导并防止高糖诱导的足细胞凋亡。

糖尿病引起的足细胞凋亡被认为在糖尿病肾病(DKD)的发病机理中起关键作用。我们提出高血糖症可以通过抑制足细胞存活因子的作用来诱导足细胞凋亡,从而使胰岛素信号的细胞作用失活。在这项研究中,我们旨在确定利格列汀对高糖诱导的足细胞凋亡的影响。利格列汀减少了高糖条件引起的足细胞DNA片段化的增加以及TUNEL阳性细胞的增加。此外,利格列汀改善了胰岛素诱导的胰岛素受体底物1(IRS1)和Akt的磷酸化,在高糖条件下被抑制。在高糖条件下,腺病毒载体介导的IRS1在足细胞中的过度表达使DNA片段化部分标准化,而使用小分子干扰RNA下调IRS1表达,即使在低葡萄糖条件下也能增加DNA片段化。由于活性氧会抑制糖尿病和肾小球样ECH相关蛋白1(Keap1)/核因子类红血球2相关因子2(Nrf2)途径中的肾小球胰岛素信号传导,因此是最重要的内在抗氧化系统之一,因此我们评估了利格列汀是否增加足细胞中的Nrf2。与低葡萄糖条件相比,高葡萄糖条件和加入利格列汀的人增加了Nrf2的水平。总之,利格列汀可通过增强足细胞中的IRS1 / Akt胰岛素信号传导并部分通过Keap1 / Nrf2途径来提供针对DKD的保护。我们的发现表明,利格列汀可能对DKD患者具有保护作用,

更新日期:2020-04-01
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