First Clinical Medical College, Xuanwu Hospital, Capital Medical University, No. 45 Changchun Street, Beijing 100053, China.
Department of Life Sciences, National Natural Science Foundation of China, No. 83 Shuangqing Road, Beijing 100085, China.
Biomed Pharmacother. 2023 Sep;165:115246. doi: 10.1016/j.biopha.2023.115246. Epub 2023 Jul 29.
Peritoneal dialysis is an efficient renal replacement therapy for patients with end-stage kidney disease. However, continuous exposure of the peritoneal membrane to dialysate frequently leads to peritoneal fibrosis, which alters the function of the peritoneal membrane and results in withdrawal from peritoneal dialysis in patients. Among others, high glucose dialysate is considered as a predisposing factor for peritoneal fibrosis in patients on peritoneal dialysis. Glucose-induced inflammation, metabolism disturbance, activation of the renin-angiotensin-aldosterone system, angiogenesis and noninflammation-induced reactive oxygen species are implicated in the pathogenesis of high glucose dialysate-induced peritoneal fibrosis. Specifically, high glucose causes chronic inflammation and recurrent peritonitis, which could cause migration and polarization of inflammatory cells, as well as release of cytokines and fibrosis. High glucose also interferes with lipid metabolism and glycolysis by activating the sterol-regulatory element-binding protein-2/cleavage-activating protein pathway and increasing hypoxia inducible factor-1α expression, leading to angiogenesis and peritoneal fibrosis. Activation of the renin-angiotensin-aldosterone system and Ras-mitogen activated protein kinase signaling pathway is another contributing factor in high glucose dialysate-induced fibrosis. Ultimately, activation of the transforming growth factor-β1/Smad pathway is involved in mesothelial-mesenchymal transition or epithelial-mesenchymal transition, which leads to the development of fibrosis. Although possible intervention strategies for peritoneal dialysate-induced fibrosis by targeting the transforming growth factor-β1/Smad pathway have occasionally been proposed, lack of laboratory evidence renders clinical decision-making difficult. We therefore aim to revisit the upstream pathways of transforming growth factor-beta1/Smad and propose potential therapeutic targets for high glucose-induced peritoneal fibrosis.
腹膜透析是治疗终末期肾病患者的一种有效肾脏替代疗法。然而，腹膜持续暴露于透析液中常导致腹膜纤维化，从而改变腹膜的功能，导致患者退出腹膜透析。其中，高糖透析液被认为是腹膜透析患者腹膜纤维化的一个诱发因素。葡萄糖诱导的炎症、代谢紊乱、肾素-血管紧张素-醛固酮系统的激活、血管生成和非炎症诱导的活性氧物质都与高糖透析液诱导的腹膜纤维化的发病机制有关。具体来说，高糖会导致慢性炎症和复发性腹膜炎，这可能导致炎症细胞的迁移和极化，以及细胞因子和纤维化的释放。高糖还通过激活固醇调节元件结合蛋白-2/切割激活蛋白途径和增加缺氧诱导因子-1α的表达来干扰脂质代谢和糖酵解，导致血管生成和腹膜纤维化。肾素-血管紧张素-醛固酮系统和 Ras-有丝分裂原激活蛋白激酶信号通路的激活也是高糖透析液诱导纤维化的另一个因素。最终，转化生长因子-β1/Smad 通路的激活涉及间皮-间充质转化或上皮-间充质转化，导致纤维化的发展。虽然通过靶向转化生长因子-β1/Smad 通路偶尔提出了针对腹膜透析液诱导纤维化的可能干预策略，但缺乏实验室证据使得临床决策变得困难。因此，我们旨在重新审视转化生长因子-β1/Smad 通路的上游通路，并为高糖诱导的腹膜纤维化提出潜在的治疗靶点。
