Hydrogen sulphide mitigates homocysteine-induced apoptosis and matrix remodelling in mesangial cells through Akt/FOXO1 signalling cascade
Hydrogen sulphide mitigates homocysteine-induced apoptosis and matrix remodelling in mesangial cells through Akt/FOXO1 signalling cascade
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DOI：
10.1016/j.cellsig.2019.05.003
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发表时间：
2019-09-01
影响因子：
4.8
通讯作者：
Sen, Utpal
中科院分区：
文献类型：
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作者：
Majumder, Suravi;Ren, Lu;Sen, Utpal
细胞损伤和细胞外基质（ECM）蛋白在肾小球间质空间的积累是慢性肾脏疾病（CKD）的标志。高同型半胱氨酸血症（HHcy），高水平的同型半胱氨酸（Hcy）与CKD相关，并进一步导致肾脏损害。尽管有大量的研究，Hcy介导的细胞损伤和ECM重塑在肾脏中的信号转导机制仍然没有定论。同型半胱氨酸代谢产生硫化氢（H2S），许多研究表明，H2S减轻了同型半胱氨酸在多种疾病中的不利影响，涉及几种信号分子，包括叉头盒O（FOXO）蛋白。FOXO是包括FOXO 1在内的一组转录因子，FOXO 1在细胞生长和增殖中起重要作用。另一方面，细胞存活因子Akt在正常条件下调节FOXO。然而，Akt/FOXO 1通路参与Hcy诱导的系膜细胞损伤仍然是难以捉摸的，H2S是否发挥任何保护作用尚未明确。我们在高同型半胱氨酸条件下，用或不用H2S供体GYY 4137和FOXO 1抑制剂AS 1842856处理小鼠系膜细胞，并确定Akt/FOXO 1信号级联的参与。我们的研究结果表明，同型半胱氨酸失活Akt和激活FOXO 1通过去磷酸化的信号分子和诱导FOXO 1核转位，然后激活FOXO 1转录因子。这些导致诱导细胞凋亡和过量ECM蛋白的合成，部分原因是ROS产生增加、线粒体膜电位（Δ Psim）损失、细胞内ATP浓度降低、MMP-2、-9、-14 mRNA和蛋白表达增加以及Col I、IV和纤连蛋白蛋白表达增加。有趣的是，GYY 4137或AS 1842856处理通过调节HHcy中的Akt/FOXO 1轴来防止这些变化。GYY 4137和/或AS 1842856通过调节Akt/FOXO 1通路减轻高同型半胱氨酸诱导的系膜细胞损伤和ECM重塑。
Cellular damage and accumulation of extracellular matrix (ECM) protein in the glomerulo-interstitial space are the signatures of chronic kidney disease (CKD). Hyperhomocysteinemia (HHcy), a high level of homocysteine (Hcy) is associated with CKD and further contributes to kidney damage. Despite a large number of studies, the signalling mechanism of Hcy-mediated cellular damage and ECM remodelling in kidney remains inconclusive. Hcy metabolizes to produce hydrogen sulphide (H2S), and a number of studies have shown that H2S mitigates the adverse effect of HHcy in a variety of diseases involving several signalling molecules, including forkhead box O (FOXO) protein. FOXO is a group of transcription factor that includes FOXO1, which plays important roles in cell growth and proliferation. On the other hand, a cell survival factor, Akt regulates FOXO under normal condition. However, the involvement of Akt/FOXO1 pathway in Hcy-induced mesangial cell damage remains elusive, and whether H2S plays any protective roles has yet to be clearly defined. We treated mouse mesangial cells with or without H2S donor, GYY4137 and FOXO1 inhibitor, AS1842856 in HHcy condition and determined the involvement of Akt/FOXO1 signalling cascades. Our results indicated that Hcy inactivated Akt and activated FOXO1 by dephosphorylating both the signalling molecules and induced FOXO1 nuclear translocation followed by activation of the FOXO1 transcription factor. These led to the induction of cellular apoptosis and synthesis of excessive ECM protein, in part, due to increased ROS production, loss of mitochondrial membrane potential (Delta Psi m), reduction in intracellular ATP concentration, increased MMP-2, -9, -14 mRNA and protein expression, and Col I, IV and fibronectin protein expression. Interestingly, GYY4137 or AS1842856 treatment prevented these changes by modulating Akt/FOXO1 axis in HHcy. We conclude that GYY4137 and/or AS1842856 mitigates HHcy induced mesangial cell damage and ECM remodelling by regulating Akt/FOXO1 pathway.