Prospective, randomized, multi-center, double-blind, controlled, two-period, two-treatment, crossover, phase II trial to evaluate the safety and efficacy of PD-protec® in peritoneal dialysis in patients with chronic renal failure

Start Date13 May 2014

Sponsor / Collaborator

Zytoprotec GmbH

100 Clinical Results associated with Zytoprotec GmbH

0 Patents (Medical) associated with Zytoprotec GmbH

Literatures (Medical) associated with Zytoprotec GmbH

01 Nov 2022·Journal of the American Society of Nephrology

FR-PO451

Author: Herzog, Rebecca ; Hoogenboom, Robin ; Bartosova, Maria ; Bestvater, Felix ; Zhang, Conghui ; Zarogiannis, Sotirios G. ; Marinovic, Iva ; Hausmann, Michael ; Krunic, Damir ; Levai, Eszter ; Ridinger, David ; Kratochwill, Klaus ; Sacnun, Juan M. ; Schmitt, Claus Peter

03 May 2022·Nephrology Dialysis Transplantation

MO711: Evaluation of an in Vitro Co-Culture Model for Studying Modulation of Cross-Talk between Endothelial and Mesothelial Cells by Cytoprotective Additives in Peritoneal Dialysis Fluids

Author: Herzog, Rebecca ; Kratochwill, Klaus ; Manuel Sacnun, Juan

AbstractBACKGROUND AND AIMSPeritoneal dialysis (PD) is a life-saving renal replacement therapy. The composition of all currently available peritoneal dialysis fluids (PDF) triggers morphological and functional changes in the peritoneal membrane. Periodic exposure leads to vasculopathy, hypervascularization and diabetes-like damage of vessels, eventually leading to failure of the technique. In vitro and in vivo studies have shown that cytoprotective additives [e.g. dipeptide alanyl-glutamine (AlaGln) or kinase inhibitor lithium chloride (LiCl)] to PDF reduce peritoneal damage in mesothelial (MC) and endothelial (EC) cells. However, it is yet unclear if potential cross talk between cells present in the peritoneal membrane mediates the observed modulation of PD-associated changes. Currently, there is no model system available to study relevant processes in these cells when in close proximity. Here, we aimed to develop a co-culture model for investigating cell-to-cell communication in a PD-relevant setting using cellular proteome and secretome analyses and investigate the effects of cytoprotective additives.METHODFor modelling the peritoneal membrane in vitro, MCs and ECs were co-cultured in transwell plates. MCs were grown in the upper compartment and primary microvascular ECs were grown in the lower compartment. PDF with or without additives, was added to the upper compartment to expose MCs directly, while the ECs below were kept in medium. Cellular proteome and secretome profiles were analysed for both cell types cultured individually or together by a quantitative mass spectrometry approach. Prior to analysis of the secretome, a combinatorial peptide ligand library coupled to beads was employed to enrich low abundant proteins and deplete high abundant proteins.RESULTSProteome analysis revealed perturbation of major cellular processes including cytoskeleton reorganization, stress response, and regulation of cell death that characterize PDF cytotoxicity. Co-cultured cells yielded differently regulated pathways following PDF exposure compared to individual cultures. Several pathways relevant for PD, such as VEGF signaling in ECs or oxidative stress response in MCs were found only under co-culture conditions. Combined analysis of proteome and secretome showed specific ligand–receptor pairs expressed only under co-culture conditions regulating some of these pathways. Differentially regulated cellular and secreted proteins after PDF exposure were related to processes like angiogenesis, immune response, or and extracellular processes such as integrin signaling. Addition of 10 mM LiCl to PDF led to modulation of VEGF and oxidative stress response pathways in ECs as well as ligand–receptor pairs involved in these pathways, possibly explaining MC–EC crosstalk during PDF exposure of these cells and the cytoprotective effect of LiCl.CONCLUSIONHarmful effects of PDF on MCs may also affect ECs, as demonstrated by our data. Interestingly, both cells type react differently when co-cultured compared to individual culture models, showing the importance of models that allow cell type interaction to mimic the in vivo conditions. We identified potential signaling axes between the cell types that could explain pathophysiological changes of the peritoneal membrane during PD treatment. We have also elucidated potential mechanisms by which the cytoprotective additive LiCl may modulate crosstalk between MCs and ECs to counteract adverse PDF effects in the local peritoneal environment. Linking local peritoneal damage with systemic vasculopathy through perturbations of PD-induced cellular crosstalk, may identify therapeutic targets to reduce the cardiovascular risk of PD patients and current limitations of the therapy.

03 May 2022·Nephrology Dialysis Transplantation

MO714: PARK7—A Novel Therapeutic Target for Peritoneal Dialysis Induced Peritoneal Membrane and Vascular Transformation

Author: Pajtók, Csenge ; Szebeni, Beata ; Bartosova, Maria ; Lévai, Eszter ; Zarogiannis, Sotirios ; Peter Schmitt, Claus ; Pap, Domonkos ; Veres-Szekely, Apor ; Szabo, Attila ; Vannay, Ádám ; Herzog, Rebecca ; Zhang, Conghui ; Marinovic, Iva ; Kratochwill, Klaus

AbstractBACKGROUND AND AIMSPatients with chronic kidney disease (CKD) suffer from increased oxidative stress, which is further aggravated in patients on peritoneal dialysis (PD). Parkinson disease protein 7 (PARK7) has antioxidant and antiapoptotic activity; its role in PD is unknown.METHODTranscriptome and proteome data sets from microdissected omental arterioles obtained from age-matched non-CKD children, children with CKD5 and children on PD with fluids containing low or high concentrations of glucose degradation products (GDP; n = 6/group) underwent PARK7 related gene set analysis (FDR < 0.05). Respective parietal peritoneal tissues (n = 60) underwent digital histomorphometry analyses. PARK7 western blotting was performed in effluents of eight children on high-GDP PD. Human umbilical endothelial cells (HUVEC) viability (MTT assay) and transepithelial electrical resistance (TER, Transwells) and 4-, 10- and 70-kDa dextran transport were measured (n = 6–12/group). As an extreme phenotype approach of PD toxicity, C57/BL6J mice were treated with chlorhexidine digluconate (CG) and PARK7 activator for 7 days and parietal peritoneal damage was quantitated (n = 6–8/group).RESULTSArteriolar transcriptome analyses in children on low-GDP PD demonstrated the enrichment of PARK7 related GO terms of oxidant detoxification as compared to CKD5 and in children on high-GDP PD that of reactive oxygen species-, mitochondria- and apoptosis-related processes. On the proteome level the DNA repair/organization, catabolic and mitochondria associated processes were enriched in children on low-GDP PD, and mitochondrial processes in children on high-GDP PD.PARK7 was detected in the parietal peritoneal tissues in mesothelial, endothelial and inflammatory cells, in myocytes and fibroblasts and was present in the PD effluents. Total peritoneal and submesothelial PARK7 abundance was similar in controls, patients with CKD5 and in patients on low-GDP PD, but 2-fold increased in patients on high GDP PD compared to controls and CKD5. Mesothelial PARK7 was 2-fold increased in children on low-GDP PD versus CKD5, endothelial PARK7 abundance was similar in all four groups.In low-GDP PD patients endothelial PARK7 abundance correlated with vessel lumen/vessel diameter ratio (r = 0.53, P = 0.06), i.e. inversely with lumen obliteration. Submesothelial PARK7 correlated with microvessel density (r = 0.55, P = 0.05), with submesothelial hypoxia inducible factor-1 and angiopoietin-1 and -2 (ρ = 0.63, P = 0.023; r = 0.91, P < 0.0001; r = 0.60, P = 0.03) but not with VEGF. Submesothelial and endothelial PARK7 correlated with respective caspase 3 abundances (r = 0.74/0.68, P = 0.009/0.015).In HUVEC methylglyoxal (MG) dose- and time-dependently reduced viability, coincubation with PARK7 activator partially preserved endothelial cell viability. In Transwells, MG treatment decreased TER and increased dextran transport, but none of them was improved by PARK7 activation.In mice treated with CG submesothelial thickness was 2-fold increased, microvessel density was unchanged; PARK7 protein abundance was 5-fold reduced. Co-treatment of CG with PARK7 activator prevented the submesothelial thickening.CONCLUSIONPD modifies arteriolar PARK7 related biological processes of oxidant detoxification, mitochondria- and apoptosis-related processes. PARK7 is ubiquitously expressed in the parietal peritoneum and regulated by the GDP content of PD fluids. In patients on low-GDP PD, PARK7 abundance correlated with the degree of arteriolar lumen narrowing, and VEGF-independent angiogenesis. Activation of PARK7 preserves endothelial cell viability in vitro and prevents CG induced peritoneal membrane damage in mice and thus represents a potential novel therapeutic approach.

100 Deals associated with Zytoprotec GmbH

100 Translational Medicine associated with Zytoprotec GmbH

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Drug(Targets)	Indications	Global Highest Phase

Alanylglutamine ( IL-17 )	Kidney Failure, Chronic More	Phase 2
ICOprotec	Peritoneal Diseases More	Preclinical

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