Hu Xiaofang, Chen Wei, Yang Ming, Li Mengwei, Li Xiangyi, Ouyang Shaxi
Hunan Normal University Health Science Center, Changsha, 410013, Hunan, People's Republic of China.
Department of Nephrology, Zhuzhou Central Hospital, Zhuzhou, 412007, People's Republic of China.
Cell Mol Life Sci. 2025 May 27;82(1):215. doi: 10.1007/s00018-025-05718-5.
Diabetic nephropathy (DN) is an important complication in diabetic patients that severely impacts their quality of life and life expectancy. Although metabolic and inflammatory responses induced by hyperglycemia are considered the primary pathogenic factors of DN, the specific molecular mechanisms involved remain unclear. Here, we investigated the role of insulin-like growth factor-binding protein 5 (IGFBP5) in DN using in vitro cell experiments and mouse models.
We assessed the effects of high-glucose conditions on IGFBP5 expression in glomerular endothelial cells and evaluated its regulatory effects on glycolysis, NLRP3 inflammasome activation, endothelial‒mesenchymal transition (EndoMT), and histone lactylation via the suppression of IGFBP5. Furthermore, we evaluated the effects of IGFBP5 on renal fibrosis and confirmed its regulatory mechanisms in DN model mice.
Knockdown of IGFBP5 inhibited high glucose-induced EndoMT in glomerular endothelial cells, which could also be suppressed by the NLRP3 inflammasome inhibitor MCC950. In addition, silencing of IGFBP5 decreased glycolytic activity and histone lactylation, thereby inhibiting the activation of the NLRP3 inflammasome and EndoMT. Furthermore, in mouse models of DN, IGFBP5 knockdown alleviated renal fibrosis and reduced glycolysis, histone lactylation, NLRP3 inflammasome activation and EndoMT.
IGFBP5 promotes NLRP3 inflammasome-induced EndoMT and renal fibrosis by regulating glycolysis-mediated histone lactylation, accelerating the progression of DN. These findings provide a new potential therapeutic target for DN.
糖尿病肾病（DN）是糖尿病患者的一种重要并发症，严重影响其生活质量和预期寿命。尽管高血糖诱导的代谢和炎症反应被认为是DN的主要致病因素，但具体的分子机制仍不清楚。在此，我们使用体外细胞实验和小鼠模型研究了胰岛素样生长因子结合蛋白5（IGFBP5）在DN中的作用。
我们评估了高糖条件对肾小球内皮细胞中IGFBP5表达的影响，并通过抑制IGFBP5来评估其对糖酵解、NLRP3炎性小体激活、内皮-间质转化（EndoMT）和组蛋白乳酸化的调节作用。此外，我们评估了IGFBP5对肾纤维化的影响，并在DN模型小鼠中证实了其调节机制。
敲低IGFBP5可抑制高糖诱导的肾小球内皮细胞EndoMT，NLRP3炎性小体抑制剂MCC950也可抑制该过程。此外，沉默IGFBP5可降低糖酵解活性和组蛋白乳酸化，从而抑制NLRP3炎性小体和EndoMT的激活。此外，在DN小鼠模型中，敲低IGFBP5可减轻肾纤维化，并减少糖酵解、组蛋白乳酸化、NLRP3炎性小体激活和EndoMT。
IGFBP5通过调节糖酵解介导的组蛋白乳酸化促进NLRP3炎性小体诱导的EndoMT和肾纤维化，加速DN的进展。这些发现为DN提供了一个新的潜在治疗靶点。
