Contribution of myo-inositol oxygenase in AGE:RAGE-mediated renal tubulointerstitial injury in the context of diabetic nephropathy.
Contribution of myo-inositol oxygenase in AGE:RAGE-mediated renal tubulointerstitial injury in the context of diabetic nephropathy.
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DOI：
10.1152/ajprenal.00434.2017
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发表时间：
2018
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影响因子：
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通讯作者：
I. Sharma;R. Tupe;Aryana K Wallner;Y. Kanwar
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作者：
I. Sharma;R. Tupe;Aryana K Wallner;Y. Kanwar
晚期糖基化终产物（AGEs）在糖尿病肾病（DN）的发病机制中起重要作用。肌醇加氧酶（MIOX）与DN的小管间质损伤有关。我们研究了AGEs对MIOX表达的影响，并描绘了导致小管间质损伤的机制。在AGE- bsa处理小鼠的肾小管细胞和肾脏中，检测了AGE:RAGE相互作用后激活的MIOX、RAGE和相关细胞信号通路的状态。固相分析显示RAGE与AGE-BSA、age -层粘连蛋白和age -胶原IV的结合增强。AGE-BSA处理的细胞增加了MIOX活性/表达和启动子活性。这与磷脂酰肌醇3-激酶(PI3K)- akt通路的多种信号激酶被激活以及NF-κ b、转化生长因子(TGF)-β和纤维连接蛋白的表达增加有关，这些表达通过MIOX/RAGE-小干扰（si） RNA处理而被否定。伴随着MIOX的上调，活性氧（ROS）的产生增加，这可以通过MIOX/RAGE- siRNA处理来消除。经AGE-BSA处理的小鼠肾脏尿A/C比显著升高，MIOX、RAGE、NF-κB水平上调，单核细胞大量涌入肾小管间质，MCP-1、IL-6、纤维连接蛋白表达增加，ROS生成增加。同时使用抑制剂MIOX或RAGE （d-glucarate和FPS-ZM1）可以消除这种干扰。这些研究支持AGE:RAGE相互作用在PI3K-AKT通路的激活和MIOX的上调中发挥作用，ROS的过量产生，NF-κB、炎症细胞因子、TGF-β和纤维连接蛋白的表达增加。总的来说，这些观察结果强调了MIOX在DN小管间质损伤中的生物学相关性。
Advanced glycation end products (AGEs) play a role in pathogenesis of diabetic nephropathy (DN). Myo-inositol oxygenase (MIOX) has been implicated in tubulointerstitial injury in the context of DN. We investigated the effect of AGEs on MIOX expression and delineated mechanisms that lead to tubulointerstitial injury. The status of MIOX, RAGE, and relevant cellular signaling pathways activated following AGE:RAGE interaction was examined in tubular cells and kidneys of AGE-BSA-treated mice. A solid-phase assay revealed an enhanced binding of RAGE with AGE-BSA, AGE-laminin, and AGE-collagen IV. The cells treated with AGE-BSA had increased MIOX activity/expression and promoter activity. This was associated with activation of various signaling kinases of phosphatidylinositol 3-kinase (PI3K)-AKT pathway and increased expression of NF-κB, transforming growth factor (TGF)-β, and fibronectin, which was negated with the treatment of MIOX/RAGE- small interfering (si) RNA. Concomitant with MIOX upregulation, there was an increased generation of reactive oxygen species (ROS), which could be abrogated with MIOX/RAGE- siRNA treatment. The kidneys of mice treated with AGE-BSA had significantly high urinary A/C ratio, upregulation of MIOX, RAGE and NF-κB, along with influx of monocytes into the tubulointerstitium, increased the expression of MCP-1, IL-6, and fibronectin and increased the generation of ROS. Such perturbations were abrogated with the concomitant treatment of inhibitors MIOX or RAGE (d-glucarate and FPS-ZM1). These studies support a role of AGE:RAGE interaction in the activation of PI3K-AKT pathway and upregulation of MIOX, with excessive generation of ROS, increased expression of NF-κB, inflammatory cytokines, TGF-β, and fibronectin. Collectively, these observations highlight the relevance of the biology of MIOX in the contribution toward tubulointerstitial injury in DN.