Zhou Jie, Yang Jie, Wang Yu-Meng, Ding Hong, Li Tu-Shuai, Liu Zhi-Hong, Chen Li, Jiao Rui-Qing, Zhang Dong-Mei, Kong Ling-Dong
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China.
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China.
Cell Signal. 2021 Oct;86:110082. doi: 10.1016/j.cellsig.2021.110082. Epub 2021 Jul 10.
Glomerular hypertrophy is a crucial factor of severe podocyte damage and proteinuria. Our previous study showed that high fructose induced podocyte injury. The current study aimed to explore a novel molecular mechanism underlying podocyte hypertrophy induced by high fructose. Here we demonstrated for the first time that high fructose significantly initiated the hypertrophy in rat glomeruli and differentiated human podocytes (HPCs). Consistently, it induced inflammatory response with the down-regulation of anti-inflammatory factor 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 microRNA-92a-3p (miR-92a-3p) and its target protein cyclin-dependent kinase inhibitor p57 (P57) down-regulation, representing abnormal proliferation and apoptosis, were observed in vivo and in vitro. Moreover, high fructose increased ketohexokinase-A (KHK-A) expression in rat glomeruli and differentiated HPCs. Exogenous IL-6 stimulation up-regulated IL-6/STAT3 signaling and miR-92a-3p, reduced P57 expression and promoted podocyte proliferation, apoptosis and hypertrophy in vitro. The data from anti-inflammatory agent maslinic acid treatment or TTP siRNA transfection showed that high fructose may decrease TTP to activate IL-6/STAT3 signaling in podocyte overproliferation and apoptosis, causing podocyte hypertrophy. Whereas, KHK-A siRNA transfection remarkably restored high fructose-induced TTP down-regulation, IL-6/STAT3 signaling activation, podocyte overproliferation, apoptosis and hypertrophy in differentiated HPCs. Taken together, these results suggested that high fructose possibly increased KHK-A expression to down-regulate TTP, subsequently activated IL-6/STAT3 signaling to interfere with podocyte proliferation and apoptosis by up-regulating miR-92a-3p to suppress P57 expression, causing podocyte hypertrophy. Therefore, the inactivation of IL-6/STAT3 to relieve podocyte hypertrophy mediated by inhibiting KHK-A to increase TTP may be a novel strategy for high fructose diet-associated podocyte injury and proteinuria.
肾小球肥大是严重足细胞损伤和蛋白尿的关键因素。我们之前的研究表明，高果糖会诱导足细胞损伤。本研究旨在探索高果糖诱导足细胞肥大的新分子机制。在此，我们首次证明高果糖显著引发大鼠肾小球和分化的人足细胞（HPCs）肥大。一致地，在这些动物和细胞模型中，它通过下调抗炎因子锌指蛋白三指四脯氨酸蛋白（TTP）诱导炎症反应，并激活白细胞介素-6（IL-6）/信号转导和转录激活因子3（STAT3）信号通路。随后，在体内和体外均观察到微小RNA-92a-3p（miR-92a-3p）的高表达及其靶蛋白细胞周期蛋白依赖性激酶抑制剂p57（P57）的下调，这代表了异常增殖和凋亡。此外，高果糖增加大鼠肾小球和分化的HPCs中酮己糖激酶-A（KHK-A）的表达。外源性IL-6刺激上调IL-6/STAT3信号通路和miR-92a-3p，降低P57表达，并在体外促进足细胞增殖、凋亡和肥大。抗炎剂山楂酸处理或TTP siRNA转染的数据表明，高果糖可能通过降低TTP来激活足细胞过度增殖和凋亡中的IL-6/STAT3信号通路，导致足细胞肥大。然而，KHK-A siRNA转染显著恢复了高果糖诱导的分化HPCs中TTP下调、IL-6/STAT3信号通路激活、足细胞过度增殖、凋亡和肥大。综上所述，这些结果表明，高果糖可能通过增加KHK-A表达来下调TTP，随后激活IL-6/STAT3信号通路，通过上调miR-92a-3p抑制P57表达来干扰足细胞增殖和凋亡，导致足细胞肥大。因此，通过抑制KHK-A增加TTP来使IL-6/STAT3失活以减轻足细胞肥大，可能是治疗高果糖饮食相关足细胞损伤和蛋白尿的新策略。
