Hydrogen Sulfide Inhibits High Glucose-induced Matrix Protein Synthesis by Activating AMP-activated Protein Kinase in Renal Epithelial Cells
Hydrogen Sulfide Inhibits High Glucose-induced Matrix Protein Synthesis by Activating AMP-activated Protein Kinase in Renal Epithelial Cells
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DOI：
10.1074/jbc.m111.278325
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发表时间：
2012-02-10
影响因子：
4.8
通讯作者：
Kasinath, Balakuntalam S.
中科院分区：
文献类型：
--
作者：
Lee, Hak Joo;Mariappan, Meenalakshmi M.;Kasinath, Balakuntalam S.
硫化氢是一种信号气体，影响多种细胞功能。我们假设硫化氢调节高糖（30 mM）刺激肾小球上皮细胞基质蛋白合成。高糖刺激的全球蛋白质合成，细胞肥大，和基质层粘连蛋白和IV型胶原蛋白的含量被抑制硫氢化钠（NaHS），H2S供体。NaHS可抑制哺乳动物雷帕霉素靶蛋白（mTOR）复合物1（mTORC 1）的高糖激活（通过p70 S6激酶和4 E-BP 1的磷酸化显示）。高葡萄糖刺激mTORC 1促进mRNA翻译起始和延伸阶段的关键事件：eIF 4A与eIF 4G的结合、PDCD 4表达减少并抑制其与eIF 4A的结合、eEF 2激酶磷酸化和eEF 2的去磷酸化;这些事件被NaHS抑制。研究了一种蛋白质合成抑制剂AMP激活蛋白激酶（AMPK）的作用。NaHS剂量依赖性地刺激AMPK磷酸化，并恢复由高糖降低的AMPK磷酸化。化合物C，AMPK抑制剂，废除NaHS调节高葡萄糖对mRNA翻译以及整体和基质蛋白合成的影响。NaHS对AMPK磷酸化的诱导被针对钙调蛋白激酶激酶β的siRNA抑制，但不被AMPK的上游激酶LKB 1抑制; STO-609，一种钙调蛋白激酶激酶β抑制剂，具有相同的效果。在1型糖尿病或2型糖尿病小鼠中，胱硫醚β-合酶和胱硫醚γ-裂解酶（硫化氢生成酶）的肾皮质含量显著降低，与肾脏肥大和基质蓄积一致。硫化氢是一种新发现的肾脏蛋白质合成调节剂，其生成减少可能导致糖尿病肾损伤。
Hydrogen sulfide, a signaling gas, affects several cell functions. We hypothesized that hydrogen sulfide modulates high glucose (30 mM) stimulation of matrix protein synthesis in glomerular epithelial cells. High glucose stimulation of global protein synthesis, cellular hypertrophy, and matrix laminin and type IV collagen content was inhibited by sodium hydrosulfide (NaHS), an H2S donor. High glucose activation of mammalian target of rapamycin (mTOR) complex 1 (mTORC1), shown by phosphorylation of p70S6 kinase and 4E-BP1, was inhibited by NaHS. High glucose stimulated mTORC1 to promote key events in the initiation and elongation phases of mRNA translation: binding of eIF4A to eIF4G, reduction in PDCD4 expression and inhibition of its binding to eIF4A, eEF2 kinase phosphorylation, and dephosphorylation of eEF2; these events were inhibited by NaHS. The role of AMP-activated protein kinase (AMPK), an inhibitor of protein synthesis, was examined. NaHS dose-dependently stimulated AMPK phosphorylation and restored AMPK phosphorylation reduced by high glucose. Compound C, an AMPK inhibitor, abolished NaHS modulation of high glucose effect on events in mRNA translation as well as global and matrix protein synthesis. NaHS induction of AMPK phosphorylation was inhibited by siRNA for calmodulin kinase kinase beta, but not LKB1, upstream kinases for AMPK; STO-609, a calmodulin kinase kinase beta inhibitor, had the same effect. Renal cortical content of cystathionine beta-synthase and cystathionine gamma-lyase, hydrogen sulfide-generating enzymes, was significantly reduced in mice with type 1 diabetes or type 2 diabetes, coinciding with renal hypertrophy and matrix accumulation. Hydrogen sulfide is a newly identified modulator of protein synthesis in the kidney, and reduction in its generation may contribute to kidney injury in diabetes.