PhD Scientific Days 2023

Budapest, 22-23 June 2023

Molecular Sciences I.

The Role of PARK7 in Peritoneal Dialysis Induced Peritoneal Membrane- and Vascular Transformation

Eszter Levai 1,2,3, Conghui Zhang 2, Apor Veres-Szekely 1,3, Maria Bartosova 2, Domonkos Pap 1,3, Iva Marinovic 2, Beata Szebeni 1,3, Rebecca Herzog 4,5, Csenge Szasz 1,3, Betti Schaefer 2, Peter Bokrossy 1,3, Klaus Kratochwill 4,5, Sotirios G. Zarogiannis 2,6, Attila J Szabo 1,3, Adam Vannay 1,3, Claus P. Schmitt 2
1 Pediatric Center, Semmelweis University, Budapest
2 Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg
3 ELKH-SE, Pediatrics and Nephrology Research Group
4 Medical University of Vienna, Christian Doppler Laboratory for Molecular Stress Research in Peritoneal Dialysis, Vienna
5 Medical University of Vienna, Division of Pediatric Nephrology and Gastroenterology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Vienna
6 University of Thessaly, Department of Physiology, Larissa, Greece

Text of the abstract

Introduction: Oxidative and carbonyl stress is prevalent in chronic kidney disease (CKD) and is further aggravated in peritoneal dialysis (PD) patients. PD fluids induce major membrane alterations, as hypervascularization, fibrosis, inflammation and vasculopathy.
Aims: We describe the role of the multifunctional Parkinson Disease Protein 7 (PARK7/DJ-1) in the setting of PD.
Methods: Omental arteriolar multiomics datasets from age-matched children (non-CKD,CKD5,low- and high GDP PD,n=6/group) underwent PARK7-related gene set analysis (FDR<0.05). PARK7 was quantified by immunohistochemistry in parietal peritoneal tissues of humans (n=60,6.4±5.3y) and C57BL/6 mice, treated 7 days with chlorhexidine-digluconate (CG) and PARK7-activator compound-23 (n=6-8/group). PARK7 activity-dependent cell viability (MTT assay) of endothelial cells (HUVEC), and secreted PARK7 levels of PD fluid treated mesothelial cells (HPMC) was measured in vitro.
Result: Arteriolar transcriptome and proteome PARK7-related GO term analysis demonstrated oxidant detoxification-, mitochondria- and apoptosis-related process enrichment in PD vs. CKD5. Peritoneal arteriolar PARK7 levels were reduced in CKD5 compared to controls, arteriolar and mesothelial PARK7 was twofold increased in children on low GDP PD compared to CKD5, submesothelial abundance twofold with high GPD PD. In low GDP PD submesothelial PARK7 correlated with microvessel density (r=0.55, p=0.05), HIF1a and Angpt1/-2 (ρ=0.63 p=0.02, r=0.91 p<0.0001, r=0.60 p=0.03), but not with VEGF. In CG treated mice doubling of submesothelial thickness was prevented by compound-23 co-treatment. Microvessel density increased in animals treated with compound-23 or with CG, but not further by the combined treatment. In vitro, GDP (methylglyoxal, 3,4-DGE) dose-dependently reduced HUVEC viability, which co-incubation with compound-23 partially preserved. PD fluids dose-dependently increased secreted PARK7 levels of HPMC, while glucose alone did not.
Conclusion: Our findings suggest a vascular and fibrotic regulatory function effect of PARK7. PARK7 represents a novel, targetable element of PD membrane- and vascular transformation.
Funding: ÚNKP-22-3-II-SE-32, SE250+ Excellence Scholarship for PhD Students, ERA EJP RD Research Mobility- and Jellinek Harry Scholarships, IMPROVE-PD European Action, STIA-KFI-2020, János Bolyai Research Scholarship of the HAS.