CKAP4在高糖腹膜透析液诱导腹膜纤维化中的作用机制及临床应用

Peritoneal dialysis(PD) is the main renal replacement treatment for end-stage renal disease(ESRD).Long term PD is limited because of the structural and functional changes in the peritoneal membrane(PM) induced by PD fluids, which contain high concentrations of glucose that final lead to a loss of ultrafiltration. Some relevant mechanism researches reported that high glucose could lead to peritoneal fibrosis and increase the apoptosis of peritoneal mesothelial cells by induced epithelial to mesenchymal transition (EMT) and oxidative stress. Cytoskeleton-associated membrane protein 4 (CKAP4), one kind of type II trans-membrane protein,plays an important role to maintain endoplasmic reticulum structure and inhibits the proliferation of cancer cells.our study reavealed that CKAP4 inhibited growth and metastasis of hepatocellular carcinoma through regulating EGFR signaling and inhibiting EMT. And we also examined the CKAP4 serum concentration in the healthy, hepatitis, cirrhosis and live cancer patients by enzyme linked immunosorbent assay (ELISA). The ELISA results shown that CKAP4 concentration was higher in the serum of hepatitis, cirrhosis, and live cancer patients compared with healthy. Futher study demostrated CKAP4 is expressed in the paritoneal membrane and upregreated in a mouse model of high glucose PD fluid exposure. But it is not clear that the effect of CKAP4 on the high glucose induced peritoneal fibrosis.Thus,we will research the relationgship between CKAP4 and peritoneal dysfuntion by induced high glucose, and examine the CKAP4 serum concentration in the peritoneal dialysis patients. it may provide therapeutic values and serum diagnostic marker for PD patients with peritoneal fibrosis.

腹膜透析是终末期肾病的主要替代治疗方式。但是长时间的腹膜透析会导致腹膜的结构和功能改变，其中高糖腹膜透析液导致的腹膜失超滤为主要原因之一。 已有研究报道高糖腹膜透析液会诱导腹膜间皮细胞上皮向间质转化(eptithelial to mesenchymal transition EMT)及氧化应激反应，导致腹膜纤维化及增加腹膜细胞的凋亡。我们前期在肝癌中研究发现细胞骨架相关膜蛋白4（CKAP4）可通过调控EGFR信号通路，抑制EMT的发生。进一步研究显示在炎症及纤维化阶段，血清中CKAP4的浓度较正常明显升高。我们的研究也表明CKAP4在高糖刺激的腹膜组织中表达升高，但CKAP4在高糖刺激导致的腹膜纤维化的作用及机制并不明确，我们将进行相关方面的研究，为高糖腹膜透析液导致的腹膜失功能提供治疗的理论依据。并分析血清中CKAP4浓度的变化情况，为临床早期诊断与早期干预提供可能。

腹膜透析是终末期肾脏病患者常用的一种肾脏替代方式。但长期腹膜透析会导致腹膜的结构和功能受损，进而导致腹膜纤维化。腹膜纤维化是腹膜透析患者腹透失超滤退出腹膜透析的的主要原因之一。其中腹膜间皮细胞上皮向间质转化（EMT）是导致腹膜纤维化的重要机制，我们前期在肝癌中研究发现细胞骨架相关膜蛋白4（CKAP4）对EMT有调控作用。前期研究也表明CKAP4在高糖刺激的小鼠腹膜组织中表达升高，这一结果提示我们CKAP4对于高糖腹膜透析液导致的腹膜纤维化可能有调控作用。因此，本课题从体内实验和体外实验以及临床标本三个方面重点探索CKAP4在腹膜透析腹膜纤维化过程中的作用及机制。研究中我们分析了随着腹膜透析时间延长CKAP4在腹膜间皮细胞中的表达情况，发现CKAP4在腹膜间皮细胞的表达量和腹膜透析时间呈正相关。为深入分析CKAP4在腹膜纤维化中的作用，我们制备了CKAP4基因敲除小鼠，我们发现在诱导小鼠腹膜纤维化过程中，CKAP4敲除后的小鼠通过抑制EMT可改善腹膜纤维化程度。为评估CKAP4作为评估腹膜功能的生物学标志的价值，我们收集了规律腹膜透析患者的血清，并分析CKAP4的血清浓度与腹膜超滤功能和透析充分性的关系，研究发现CKAP4血清浓度升高预示着腹膜超滤功能下降和透析充分性下降。CKAP4有望作为评估腹膜纤维化的血清生物学标志物。