Inhibition of intra-peritoneal carbonyl stress by carbonyl adsorbing beads or carbonyl stress inhibitor

羰基吸附珠或羰基应激抑制剂对腹腔内羰基应激的抑制

基本信息

批准号：
17590847
负责人：
KAKUTA Takatoshi
金额：
$ 2.37万
依托单位：
Tokai University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

The molecular mechanisms underlying the peritoneal membrane (PM) failure remain elusive. Chronic uremia by itself modifies the PM and increases the effective peritoneal surface area (EPSA). PM deterioration during peritoneal Dialysis (PD) results, at least in part, from the accumulation of reactive carbonyl compounds (RCOs) present in heat-sterilized PD fluid. We have proposed two hypothetical approaches to reduce intra-peritoneal carbonyl stress. The more recently identified pyridoxamine, ARB and its analog a new class of advanced glycation end products (AGEs) inhibitors, traps RCO precursors by its amino group. Another approach to reduce intra-peritoneal carbonyl stress is the RCO adsorbing beads. Pyridoxamine, given in uremic rats with PD, significantly improved functional and structural alterations. This improvement was accompanied by reduction of AGE accumulation and of angiogenic cytokines expressions. Mixed with glucose PD fluid, pyrazolinones-polyethyleneimine, with cellulose beads (PPCB) markedly lowers RCOs (??dicarbonyls and aldehydes) and inhibits the generation of pentosidine, an AGE, to levels similar to those of filter-sterilized PD fluid. Its effectiveness is more than one order of magnitude above those of previously developed beads.

腹膜（PM）衰竭的分子机制仍然难以捉摸。慢性尿毒症本身会改变 PM 并增加有效腹膜表面积 (EPSA)。腹膜透析 (PD) 过程中 PM 的恶化至少部分是由热灭菌腹膜透析液中活性羰基化合物 (RCO) 的积累造成的。我们提出了两种减少腹膜内羰基应激的假设方法。最近发现的吡哆胺、ARB 及其类似物是一种新型高级糖基化终末产物 (AGE) 抑制剂，通过其氨基捕获 RCO 前体。另一种减少腹膜内羰基应激的方法是 RCO 吸附珠。吡哆胺给予患有帕金森病的尿毒症大鼠，显着改善了功能和结构的改变。这种改善伴随着 AGE 积累和血管生成细胞因子表达的减少。与葡萄糖腹膜透析液、吡唑啉酮-聚乙烯亚胺和纤维素珠 (PPCB) 混合，可显着降低 RCO（二羰基和醛类）并抑制戊糖苷（一种 AGE）的生成，使其水平与过滤灭菌腹膜透析液相似。其有效性比之前开发的珠子高出一个数量级以上。