Liu Xuan, Zhou Donghui, Su Yu, Liu Hongling, Su Qiuyue, Shen Tianyu, Zhang Mianzhi, Mi Xue, Zhang Yuying, Yue Shijing, Zhang Zhujun, Wang Dekun, Tan Xiaoyue
Department of Pathology, School of Medicine, Nankai University, Tianjin, China.
Dongfang Hospital of Beijing University of Chinese medicine, Beijing, China.
Biochim Biophys Acta Mol Basis Dis. 2025 Mar;1871(3):167645. doi: 10.1016/j.bbadis.2024.167645. Epub 2024 Dec 30.
The role of ER stress in the pathogenesis of diabetic kidney diseases (DKD) remains unclear. We employed bioinformatics to identify the UPR pathway activation, inflammation, and programmed cell death patterns in diabetic tubules. Levels of IRE1α/sXBP1 signaling, NLRP3 inflammasome activity and pyroptosis in tubular cells under high glucose conditions were measured. IRE1α knockdown was used to determine its role in glucose-triggered activation of the NLRP3 inflammasome and pyroptosis. PDIA4 overexpression and silencing were used to assess its impact on the IRE1α/sXBP1 pathway. The dynamic interaction among PDIA4, GRP78, and IRE1α under high glucose were analyzed using immunoprecipitation and crosslinking assays. In STZ-induced and db/db mouse models of DKD, the regulatory role of PDIA4 on IRE1α/sXBP1 signaling and diabetic tubular inflammation and injury were evaluated. Our study showed that IRE1α/sXBP1, NLRP3 inflammasome, and pyroptosis are activated in the renal tubules of DKD patients. Induction of IRE1α pathway mediated the glucose-triggered activation of the NLRP3 inflammasome and pyroptosis. Moreover, overexpression of PDIA4 decreased the activation of IRE1α/sXBP1 under high glucose conditions. High glucose leads to the release of GRP78 from IRE1α and an increased interaction between IRE1α and PDIA4. In mouse models of DKD, overexpressing PDIA4 mitigated diabetic tubular injury and inflammation, marked by decreased IRE1α/sXBP1 and NLRP3 inflammasome. In conclusion, our findings demonstrate that high glucose triggers NLRP3 inflammasome and pyroptosis via the IRE1α/sXBP1 pathway in renal tubular cells. Overexpression of PDIA4 suppresses IRE1α signaling by binding to its oligomeric form, implying a promising therapeutic intervention for DKD.
内质网应激在糖尿病肾病（DKD）发病机制中的作用仍不清楚。我们运用生物信息学方法来识别糖尿病肾小管中的未折叠蛋白反应（UPR）途径激活、炎症和程序性细胞死亡模式。检测了高糖条件下肾小管细胞中IRE1α/sXBP1信号通路水平、NLRP3炎性小体活性和细胞焦亡情况。采用IRE1α基因敲低来确定其在葡萄糖触发的NLRP3炎性小体激活和细胞焦亡中的作用。通过PDIA4过表达和沉默来评估其对IRE1α/sXBP1途径的影响。利用免疫沉淀和交联试验分析高糖条件下PDIA4、GRP78和IRE1α之间的动态相互作用。在链脲佐菌素诱导的和db/db DKD小鼠模型中，评估了PDIA4对IRE1α/sXBP1信号通路以及糖尿病肾小管炎症和损伤的调节作用。我们的研究表明，IRE1α/sXBP1、NLRP3炎性小体和细胞焦亡在DKD患者的肾小管中被激活。IRE1α途径的诱导介导了葡萄糖触发的NLRP3炎性小体激活和细胞焦亡。此外，PDIA4过表达降低了高糖条件下IRE1α/sXBP1的激活。高糖导致GRP78从IRE1α释放，并增加IRE1α与PDIA4之间的相互作用。在DKD小鼠模型中，过表达PDIA4减轻了糖尿病肾小管损伤和炎症，表现为IRE1α/sXBP1和NLRP3炎性小体减少。总之，我们的研究结果表明，高糖通过肾小管细胞中的IRE1α/sXBP1途径触发NLRP3炎性小体和细胞焦亡。PDIA4过表达通过与其寡聚形式结合抑制IRE1α信号通路，这意味着对DKD有前景的治疗干预措施。
