Cohen-Hagai Keren, Kashua Hadil, Benchetrit Sydney, Zitman-Gal Tali
Department of Nephrology and Hypertension, Meir Medical Center, Kfar Saba 44281, Israel.
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Antioxidants (Basel). 2023 May 17;12(5):1109. doi: 10.3390/antiox12051109.
Endothelial dysfunction, vascular inflammation and accelerated atherosclerosis have been investigated extensively in patients with chronic kidney disease (CKD). These conditions, as well as protein-energy malnutrition and oxidative stress, impair kidney function and contribute to increased morbidity and mortality among patients with end-stage kidney disease undergoing hemodialysis (HD). TXNIP, a key regulator of oxidative stress, has been linked to inflammation and suppresses eNOS activity. STAT3 activation adds to endothelial cell dysfunction, macrophage polarization, immunity and inflammation. Therefore, it is critically involved in atherosclerosis. This study evaluated the effect of sera from HD patients on the TXNIP-eNOS-STAT3 pathway using an in vitro model of human umbilical vein endothelial cells (HUVECs).
Thirty HD patients with end-stage kidney disease and ten healthy volunteers were recruited. Serum samples were taken at dialysis initiation. HUVECs were treated with HD or healthy serum (10% /) for 24 h. Then, cells were collected for mRNA and protein analysis.
TXNIP mRNA and protein expression were significantly increased in HUVECs treated with HD serum compared to healthy controls (fold changes: 2.41 ± 1.84 vs. 1.41 ± 0.5 and 2.04 ± 1.16 vs. 0.92 ± 0.29, respectively), as were IL-8 mRNA (fold changes: 2.22 ± 1.09 vs. 0.98 ± 0.64) and STAT3 protein expression (fold changes: 1.31 ± 0.75 vs. 0.57 ± 0.43). The expression of eNOS mRNA and protein (fold changes: 0.64 ± 0.11 vs. 0.95 ± 0.24; 0.56 ± 0.28 vs. 4.35 ± 1.77, respectively) and that of SOCS3 and SIRT1 proteins were decreased. Patients' nutritional status, reflected by their malnutrition-inflammation scores, did not affect these inflammatory markers.
This study showed that sera from HD patients stimulated a novel inflammatory pathway, regardless of their nutritional status.
慢性肾脏病（CKD）患者的内皮功能障碍、血管炎症和动脉粥样硬化加速已得到广泛研究。这些情况，以及蛋白质能量营养不良和氧化应激，会损害肾功能，并导致接受血液透析（HD）的终末期肾病患者的发病率和死亡率增加。硫氧还蛋白相互作用蛋白（TXNIP）是氧化应激的关键调节因子，与炎症有关，并抑制内皮型一氧化氮合酶（eNOS）的活性。信号转导和转录激活因子3（STAT3）的激活会加重内皮细胞功能障碍、巨噬细胞极化、免疫和炎症。因此，它在动脉粥样硬化中起关键作用。本研究使用人脐静脉内皮细胞（HUVECs）的体外模型评估了HD患者血清对TXNIP-eNOS-STAT3通路的影响。
招募了30名终末期肾病的HD患者和10名健康志愿者。在透析开始时采集血清样本。将HUVECs用HD血清或健康血清（10%）处理24小时。然后，收集细胞进行mRNA和蛋白质分析。
与健康对照相比，用HD血清处理的HUVECs中TXNIP mRNA和蛋白质表达显著增加（倍数变化分别为：2.41±1.84对1.41±0.5和2.04±1.16对0.92±0.29），白细胞介素-8（IL-8）mRNA（倍数变化：2.22±1.09对0.98±0.64）和STAT3蛋白质表达（倍数变化：1.31±0.75对0.57±0.43）也是如此。eNOS mRNA和蛋白质的表达（倍数变化分别为：0.64±0.11对0.95±0.24；0.56±0.28对4.35±1.77）以及细胞因子信号转导抑制因子3（SOCS3）和沉默信息调节因子1（SIRT1）蛋白质的表达均降低。患者的营养不良炎症评分所反映的营养状况并未影响这些炎症标志物。
本研究表明，HD患者的血清刺激了一条新的炎症通路，而与他们的营养状况无关。
