Complement Activation in Peritoneal Dialysis-Induced Arteriolopathy
Complement Activation in Peritoneal Dialysis-Induced Arteriolopathy
复制标题
DOI：
10.1681/asn.2017040436
复制
发表时间：
2018-01-01
影响因子：
13.6
通讯作者：
Schmitt, Claus Peter
中科院分区：
文献类型：
--
作者：
Bartosova, Maria;Schaefer, Betti;Schmitt, Claus Peter
心血管疾病（CVD）是CKD患者死亡率增加的主要原因，腹膜透析（PD）会进一步加重心血管疾病。儿童没有预先存在的CVD，并提供了独特的见解，具体尿毒症和PD诱导的CVD的病理机制。我们从PD导管插入时的5期CKD儿童（CKD 5组）、确诊PD的儿童（PD组）和年龄匹配的非尿毒症对照组（n=6/组）中获得腹膜标本。我们从没有直接暴露于腹膜透析液的组织层中显微解剖网膜小动脉，并使用每位患者四条小动脉的相邻切片进行转录组学和蛋白质组学分析。在独立儿科对照（n=5）、CKD 5（n=15）和PD（n=15）队列的网膜和顶叶小动脉中验证了结果。转录组学分析揭示了对照与CKD 5小动脉和CKD 5与PD小动脉中的差异基因表达。基因本体分析显示CKD 5小动脉中的代谢过程和PD小动脉中的炎症、免疫和应激反应级联的活化。PD小动脉表现出特定的补体系统和各自的调节途径的上调，在蛋白质组水平的一致的结果。在验证队列中，PD标本的网膜和壁小动脉C1 q、C3 d、末端补体复合物和磷酸化SMAD 2/3（TGF-β的下游效应物）丰度最高。此外，在PD壁小动脉中，C1 q和末端补体复合物丰度与透析葡萄糖暴露水平、磷酸化SMAD 2/3丰度和血管病变程度相关。我们得出结论，腹膜透析液激活小动脉补体和TGF-β信号，这与小动脉血管病变的严重程度定量相关。
Cardiovascular disease (CVD) is the leading cause of increased mortality in patients with CKD and is further aggravated by peritoneal dialysis (PD). Children are devoid of preexisting CVD and provide unique insight into specific uremia-and PD-induced pathomechanisms of CVD. We obtained peritoneal specimens from children with stage 5 CKD at time of PD catheter insertion (CKD5 group), children with established PD (PD group), and age-matched nonuremic controls (n=6/group). We microdissected omental arterioles from tissue layers not directly exposed to PD fluid and used adjacent sections of four arterioles per patient for transcriptomic and proteomic analyses. Findings were validated in omental and parietal arterioles from independent pediatric control (n=5), CKD5 (n=15), and PD (n=15) cohorts. Transcriptomic analysis revealed differential gene expression in control versus CKD5 arterioles and in CKD5 versus PD arterioles. Gene ontology analyses revealed activation of metabolic processes in CKD5 arterioles and of inflammatory, immunologic, and stress-response cascades in PD arterioles. PD arterioles exhibited particular upregulation of the complement system and respective regulatory pathways, with concordant findings at the proteomic level. In the validation cohorts, PD specimens had the highest abundance of omental and parietal arteriolar C1q, C3d, terminal complement complex, and phosphorylated SMAD2/3, a downstream effector of TGF-beta. Furthermore, in the PD parietal arterioles, C1q and terminal complement complex abundance correlated with the level of dialytic glucose exposure, abundance of phosphorylated SMAD2/3, and degree of vasculopathy. We conclude that PD fluids activate arteriolar complement and TGF-beta signaling, which quantitatively correlate with the severity of arteriolar vasculopathy.