Zhu Nan, Wang Ling, Guo Huimin, Jia Jieshuang, Gu Lijie, Wang Xuan, Yang Man, Guan Haochen, Yuan Weijie
Department of Nephrology, Shanghai General Hospital, Shanghai, China.
Department of Nuclear Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong, China.
Front Physiol. 2021 Sep 3;12:712147. doi: 10.3389/fphys.2021.712147. eCollection 2021.
Peritoneal angiogenesis is the key pathophysiological factor that limits peritoneal ultrafiltration during peritoneal dialysis (PD) in uremic patients. Thalidomide has been confirmed to inhibit angiogenesis by inhibiting the secretion of vascular endothelial growth factor (VEGF), but the exact mechanism by which thalidomide inhibits vascular proliferation during PD is still unclear. Here, the objective of the present study was to investigate whether the reduction in VEGF production by human peritoneal mesothelial cells (HPMCs) was controlled by thalidomide. Stimulation of HPMCs with IL-6 in combination with soluble IL-6 receptor (sIL-6R) promoted VEGF expression and secretion, but these effects were attenuated by thalidomide treatment through a transcriptional mechanism that involved signal transducer and activator of transcription 3 (STAT3) and SP4. Conditioned medium from HPMCs cultured with thalidomide inhibited angiogenic endothelial tube formation, which could be further blocked by silencing SP4 and promoted by overexpressing SP4. , induction of peritoneal angiogenesis in sham rats, sham+PD rats, 5/6 nephrectomy (5/6Nx) rats, 5/6Nx+PD rats, and 5/6Nx+PD rats intraperitoneally treated with thalidomide showed that thalidomide was involved in the control of several key endothelial-specific targets, including , , , and expression and new vessel formation, confirming the role of thalidomide and STAT3/SP4 signaling in these processes. Taken together, these findings identify a novel mechanism that links thalidomide, STAT3/SP4 signaling, and angiogenesis in the peritoneal membrane.
腹膜血管生成是限制尿毒症患者腹膜透析（PD）期间腹膜超滤的关键病理生理因素。沙利度胺已被证实可通过抑制血管内皮生长因子（VEGF）的分泌来抑制血管生成，但沙利度胺在PD期间抑制血管增殖的确切机制仍不清楚。在此，本研究的目的是探讨沙利度胺是否能控制人腹膜间皮细胞（HPMC）产生VEGF的减少。用白细胞介素-6（IL-6）联合可溶性IL-6受体（sIL-6R）刺激HPMC可促进VEGF的表达和分泌，但这些作用通过涉及信号转导和转录激活因子3（STAT3）和SP4的转录机制被沙利度胺处理减弱。用沙利度胺培养的HPMC条件培养基可抑制血管生成性内皮管形成，沉默SP4可进一步阻断这种作用，而过表达SP4则可促进这种作用。在假手术大鼠、假手术+PD大鼠、5/6肾切除（5/6Nx）大鼠、5/6Nx+PD大鼠以及腹腔注射沙利度胺的5/6Nx+PD大鼠中诱导腹膜血管生成表明，沙利度胺参与控制几个关键的内皮细胞特异性靶点，包括 、 、 和 的表达以及新血管形成，证实了沙利度胺和STAT3/SP4信号在这些过程中的作用。综上所述，这些发现确定了一种将沙利度胺、STAT3/SP4信号和腹膜血管生成联系起来的新机制。
