Complement Activation in Peritoneal Dialysis-Induced Arteriolopathy

被引:35
作者
Bartosova, Maria [1 ]
Schaefer, Betti [1 ]
Bermejo, Justo Lorenzo [2 ]
Tarantino, Silvia [4 ]
Lasitschka, Felix [3 ]
Macher-Goeppinger, Stephan [6 ]
Sinn, Peter [3 ]
Warady, Bradley A. [7 ]
Zaloszyc, Ariane [8 ]
Parapatics, Katja [9 ]
Majek, Peter [9 ]
Bennett, Keiryn L. [9 ]
Oh, Jun [10 ]
Aufricht, Christoph [4 ]
Schaefer, Franz [1 ]
Kratochwill, Klaus [4 ,5 ]
Schmitt, Claus Peter [1 ]
机构
[1] Heidelberg Univ, Ctr Pediat & Adolescent Med, Div Pediat Nephrol, Heidelberg, Germany
[2] Heidelberg Univ, Dept Med Biometry, Inst Med Biometry & Informat, Heidelberg, Germany
[3] Heidelberg Univ, Dept Gen Pathol, Inst Pathol, Heidelberg, Germany
[4] Med Univ Vienna, Dept Pediat & Adolescent Med, Vienna, Austria
[5] Med Univ Vienna, Christian Doppler Lab Mol Stress Res Peritoneal D, Vienna, Austria
[6] Univ Med Ctr Mainz, Dept Pathol, Mainz, Germany
[7] Univ Missouri, Sch Med, Childrens Mercy Hosp, Div Pediat Nephrol, Kansas City, MO 64108 USA
[8] Univ Hosp Strasbourg, Dept Pediat 1, Strasbourg, France
[9] Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria
[10] Univ Med Ctr Hamburg Eppendorf, Dept Pediat Nephrol, Hamburg, Germany
来源
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY | 2018年 / 29卷 / 01期
关键词
GLYCATION END-PRODUCTS; CHRONIC-RENAL-FAILURE; GLUCOSE DEGRADATION-PRODUCTS; MESOTHELIAL CELLS; RESISTANCE ARTERIES; STANDARD FLUID; YOUNG-ADULTS; NEUTRAL-PH; CHILDREN; MEMBRANE;
D O I
10.1681/ASN.2017040436
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:268 / 282
页数:15
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