Wu Can, Ma Xiaoyu, Zhou Yang, Liu Yv, Shao Ying, Wang Qiuyue
Department of Endoscope, The First Hospital Affiliated to China Medical University, Shenyang, Liaoning, China.
Cadre Department, The First Hospital Affiliated to China Medical University, Shenyang, Liaoning, China.
Exp Clin Endocrinol Diabetes. 2019 Oct;127(9):630-640. doi: 10.1055/s-0044-101601. Epub 2018 Jun 11.
Anti-aging protein Klotho is closely associated with a variety of chronic diseases and age-related diseases. And Klotho gene deficiency enhances the phosphorylation of mammalian target of rapamycin (mTOR), resulting in exacerbating streptozotocin-stimulated diabetic glomerular injury and promoting the progression of early diabetic kidney disease (DKD). However, it has not yet been elucidated that the mechanism of Klotho function on the pathogenesis of diabetic glomerular injury. What's more, insulin represents the antilipolytic effect via the mTOR-early growth response factor 1 (Egr1) regulatory axis in mammalian organism. Valsartan reduced the high glucose-activated toll like report 4 (TLR4) expression and inflammatory cytokines via inhibiting Egr1 expression. In this study, we aim to explore the effects of Klotho on Egr1 expression and TLR4/mTOR pathways activity in high glucose cultured rat mesangial cells (RMCs) in vitro. Our study revealed that high glucose upregulated Egr1 to aggravate the inflammation and fibrosis in RMCs. And high glucose activates Egr1/TLR4/mTOR regulatory axis in MCs, indicating that one coherent feedforward loop is formed. Anti-aging protein Klotho may attenuate glomerular inflammation and fibrosis to provide protection against diabetic kidney injury via inhibiting the activity of Egr1/TLR4/mTOR regulatory axis in high glucose conditions. This study complements the function mechanism of Egr1/TLR4/mTOR regulatory axis playing in the pathogenesis of DKD, and provides a new direction and theoretical basis for anti-aging protein Klotho in DKD treatment.
抗衰老蛋白α-klotho与多种慢性疾病和年龄相关疾病密切相关。α-klotho基因缺陷会增强雷帕霉素靶蛋白（mTOR）的磷酸化，导致链脲佐菌素诱导的糖尿病性肾小球损伤加剧，并促进早期糖尿病肾病（DKD）的进展。然而，α-klotho在糖尿病性肾小球损伤发病机制中的作用机制尚未阐明。此外，在哺乳动物机体中，胰岛素通过mTOR-早期生长反应因子1（Egr1）调节轴发挥抗脂解作用。缬沙坦通过抑制Egr1表达，降低高糖激活的Toll样受体4（TLR4）表达和炎性细胞因子。在本研究中，我们旨在探讨α-klotho对体外高糖培养的大鼠系膜细胞（RMCs）中Egr1表达以及TLR4/mTOR信号通路活性的影响。我们的研究表明，高糖上调Egr1表达，加重RMCs的炎症和纤维化。并且高糖激活了系膜细胞中的Egr1/TLR4/mTOR调节轴，表明形成了一个连贯的前馈环。抗衰老蛋白α-klotho可能通过在高糖条件下抑制Egr1/TLR4/mTOR调节轴的活性，减轻肾小球炎症和纤维化，从而为糖尿病肾损伤提供保护。本研究补充了Egr1/TLR4/mTOR调节轴在DKD发病机制中的作用机制，并为抗衰老蛋白α-klotho在DKD治疗中的应用提供了新的方向和理论依据。
