Complement Activation in Peritoneal Dialysis-Induced Arteriolopathy
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Complement Activation in Peritoneal Dialysis-Induced Arteriolopathy. / Bartosova, Maria; Schaefer, Betti; Bermejo, Justo Lorenzo; Tarantino, Silvia; Lasitschka, Felix; Macher-Goeppinger, Stephan; Sinn, Peter; Warady, Bradley A; Zaloszyc, Ariane; Parapatics, Katja; Májek, Peter; Bennett, Keiryn L; Oh, Jun; Aufricht, Christoph; Schaefer, Franz; Kratochwill, Klaus; Schmitt, Claus Peter.
In: J AM SOC NEPHROL, 18.10.2017.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Complement Activation in Peritoneal Dialysis-Induced Arteriolopathy
AU - Bartosova, Maria
AU - Schaefer, Betti
AU - Bermejo, Justo Lorenzo
AU - Tarantino, Silvia
AU - Lasitschka, Felix
AU - Macher-Goeppinger, Stephan
AU - Sinn, Peter
AU - Warady, Bradley A
AU - Zaloszyc, Ariane
AU - Parapatics, Katja
AU - Májek, Peter
AU - Bennett, Keiryn L
AU - Oh, Jun
AU - Aufricht, Christoph
AU - Schaefer, Franz
AU - Kratochwill, Klaus
AU - Schmitt, Claus Peter
N1 - Copyright © 2017 by the American Society of Nephrology.
PY - 2017/10/18
Y1 - 2017/10/18
N2 - 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-β 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-β signaling, which quantitatively correlate with the severity of arteriolar vasculopathy.
AB - 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-β 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-β signaling, which quantitatively correlate with the severity of arteriolar vasculopathy.
KW - Journal Article
U2 - 10.1681/ASN.2017040436
DO - 10.1681/ASN.2017040436
M3 - SCORING: Journal article
C2 - 29046343
JO - J AM SOC NEPHROL
JF - J AM SOC NEPHROL
SN - 1046-6673
ER -