Han Rang-Yue, Tan Rui-Zhi, Xu Ling-Hui, Lin Jing-Yi, Li Tong, Su Hong-Wei, Li Ping, Liu Peng, Lan Hui-Yao, Wang Li
Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, China.
Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, China; Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, 646000, China.
Redox Biol. 2025 Jul 8;85:103762. doi: 10.1016/j.redox.2025.103762.
Sclerostin (Sost) functions as an inhibitor of the Wnt/β-catenin signaling pathway, which is known to promote kidney cell epithelial-to-mesenchymal transition (EMT), and fibrosis in chronic kidney disease (CKD). However, the renoprotective effects of Sost in kidney diseases and its therapeutic potential as a target remain unknown. To clarify the protective role of Sost in CKD kidneys, we utilized ultrasound microbubble-mediated renal in situ gene transfection to overexpress and knockdown Sost in kidney. Subsequently, we employed the TurboID-based protein interaction technique to screen for Sost-binding proteins and combined it with ECAR/OCR to elucidate the regulation of glycolytic pathways by Sost and its binding proteins. Sost is predominantly expressed in renal tubules and that its expression is significantly diminished in renal tissues of CKD patients, as well as in UUO and folic acid (FA) induced CKD mouse. Overexpression of Sost in vivo and in vitro ameliorated tubular injury and fibrosis. Employing the TurboID technique, we uncovered an interaction between Sost and the potential glycolysis-associated protein Isg20, an interferon-stimulated ribonuclease. This binding interaction serves to inhibit Isg20-mediated aerobic glycolysis and subsequent fibrosis within the kidney of CKD. For Sost agonists screening, we found that HDG exerts salient anti-fibrotic and renal protective effects in CKD, which are likely attributable to its significant upregulation of Sost expression, thereby inhibiting Isg20-mediated glycolysis. In summary, we demonstrate that upregulation of Sost by HDG inhibits glycolysis and renal fibrosis in CKD through binding and suppressing of Isg20, and targeting Sost may develop novel approaches to treat CKD.
硬化蛋白（Sost）作为Wnt/β-连环蛋白信号通路的抑制剂发挥作用，已知该信号通路会促进肾细胞上皮-间充质转化（EMT）以及慢性肾脏病（CKD）中的纤维化。然而，Sost在肾脏疾病中的肾脏保护作用及其作为靶点的治疗潜力仍不清楚。为了阐明Sost在CKD肾脏中的保护作用，我们利用超声微泡介导的肾脏原位基因转染在肾脏中过表达和敲低Sost。随后，我们采用基于TurboID的蛋白质相互作用技术筛选与Sost结合的蛋白质，并将其与细胞外酸化率（ECAR）/氧消耗率（OCR）相结合，以阐明Sost及其结合蛋白对糖酵解途径的调节作用。Sost主要在肾小管中表达，并且在CKD患者的肾组织以及单侧输尿管梗阻（UUO）和叶酸（FA）诱导的CKD小鼠中其表达显著降低。在体内和体外过表达Sost可改善肾小管损伤和纤维化。利用TurboID技术，我们发现Sost与潜在的糖酵解相关蛋白Isg20（一种干扰素刺激的核糖核酸酶）之间存在相互作用。这种结合相互作用可抑制Isg20介导的有氧糖酵解以及CKD肾脏中的后续纤维化。对于Sost激动剂筛选，我们发现HDG在CKD中发挥显著的抗纤维化和肾脏保护作用，这可能归因于其显著上调Sost表达，从而抑制Isg20介导的糖酵解。总之，我们证明HDG上调Sost可通过结合并抑制Isg20来抑制CKD中的糖酵解和肾纤维化，并且靶向Sost可能开发出治疗CKD的新方法。
