Glomerular hypertrophy is crucial for podocyte damage and proteinuria. Our previous study showed that fructose induced podocyte injury. However, the molecular mechanism underlying podocyte hypertrophy under fructose is unclear. We observed that fructose significantly initiated the hypertrophy in rat glomeruli and cultured differentiated human podocytes (HPCs). Consistently, it induced inflammatory response with the down-regulation of zinc-finger protein tristetraprolin (TTP) and the activation of interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling in these animal and cell models. Subsequently, high-expression of miR-92a-3p and its target protein cyclin-dependent kinase inhibitor p57 (P57) down-regulation, representing the abnormal proliferation and apoptosis, were observed in vivo and in vitro. Moreover, fructose increased ketohexokinase-A (KHK-A) in rat glomeruli and HPCs. Animal-free recombinant human IL-6 , maslinic acid and TTP siRNA were used to manifest that fructose may decrease TTP to activate IL-6/STAT3 signaling in podocyte overproliferation and apoptosis, causing podocyte hypertrophy. KHK-A siRNA transfection further demonstrated that the inactivation of IL-6/STAT3 to relieve podocyte hypertrophy mediated by inhibiting KHK-A to increase TTP may be a novel strategy for fructose-associated podocyte injury and proteinuria.

中文翻译：

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增加的酮己酮激酶-A通过IL-6 / STAT3信号激活控制果糖诱导的足细胞肥大

肾小球肥大对于足细胞损伤和蛋白尿至关重要。我们以前的研究表明，果糖可引起足细胞损伤。然而，果糖下足细胞肥大的分子机制尚不清楚。我们观察到果糖显着启动了大鼠肾小球的肥大，并培养了分化的人足细胞（HPC）。一致地，在这些动物和细胞模型中，它通过下指锌蛋白tristetraprolin（TTP）的下调以及白介素6（IL-6）/信号转导子和转录激活因子3（STAT3）信号的激活诱导炎症反应。 。随后，在体内和体外观察到高表达的miR-92a-3p及其靶蛋白细胞周期蛋白依赖性激酶抑制剂p57（P57）的下调，代表异常的增殖和凋亡。此外，果糖可增加大鼠肾小球和HPC中的ketohexokinase-A（KHK-A）。用无动物的重组人IL-6，山梨酸和TTP siRNA来证明果糖可能降低TTP以激活足细胞过度增殖和凋亡中的IL-6 / STAT3信号传导，从而引起足细胞肥大。KHK-A siRNA转染进一步证明，通过抑制KHK-A升高TTP介导的IL-6 / STAT3失活以减轻足细胞肥大可能是果糖相关足细胞损伤和蛋白尿的新策略。