PhD Scientific Days 2022

Molecular Sciences V.

PARK7 – A Potential Therapeutic Target for Peritoneal Dialysis Induced Peritoneal Membrane Transformation

Text of the abstract

Introduction
Oxidative stress is prevalent in chronic kidney disease (CKD) and is further aggravated in peritoneal dialysis (PD) patients. The role of antioxidant, antiapoptotic Parkinson Disease Protein 7 (PARK7) in PD is yet unknown.
Aims
We aimed to reveal the therapeutic potential of PARK7 protein in the peritoneum and during peritoneal dialysis.
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 Western Blotting in effluents (n=8, high-GDP PD) and by immunohistochemistry in tissues of humans (n=60). PARK7 activity-dependent viability (MTT assay) and transepithelial electrical resistance (TER) were measured in-vitro in endothelial cells (HUVEC) with the administration of a PARK7-activator compound.
Result
Arteriolar transcriptome and proteome PARK7-related GO term analysis demonstrated oxidant detoxification-, mitochondria- and apoptosis-related process enrichment in low- and high-GDP PD versus CKD5. PARK7 was detectable in all effluents. Total peritoneal PARK7 abundance is increased in children on PD compared to CKD5, with 2-fold high abundance in mesothelial PARK7 with low-GDP and 2-fold in submesothelial abundance with high-GPD PD. In low-GDP PD endothelial PARK7 abundance, correlated with vessel lumen/diameter ratio (r=0.53, p=0.06), therefore inversely with lumen obliteration. Submesothelial PARK7 correlated with microvessel density (r=0.55, p=0.05), hypoxia inducible factor-1 and angiopoietin 1 and -2 (ρ=0.63 p=0.02, r=0.91 p<0.0001, r=0.60 p=0.03), but not with VEGF. Methylglyoxal dose-dependently reduced HUVEC viability and TER, co-incubation with compound partially preserved viability, but not TER.
Conclusion
In children, peritoneal PARK7 is increased by PD and in low-GDP PD correlated with vascular lumen narrowing and VEGF-independent angiogenesis. Our histological and in vitro studies suggest PARK7 as a potential key-molecule in the membrane- and vascular damage of the peritoneum during peritoneal dialysis.
Funding
The project was funded by the Jellinek-Harry Foundation, EJP RD ERN Research Mobility Fellowship under the ERKNET Network, Semmelweis 250+ Excellence Program (EFOP-3.6.3.-VEKOP-16-2017-00009) and 2020-4.1.1-TKP2020, STIA-KFI-2020, 20382-3/2018 FEKUTSTRAT, K124549, K125470 grants.