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Published on: July 19, 2018
Bicarbonate buffered peritoneal dialysis fluid upregulates angiopoietin-1 and promotes vessel maturation
Gwendolyn Eich1, Maria Bartosova1, Christian Tischer2
1Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
Insights
Bicarbonate buffered peritoneal dialysis fluid promotes vessel maturation by increasing angiopoietin-1, preserving ultrafiltration in dialysis patients. This study reveals the molecular mechanism behind improved ultrafiltration with bicarbonate buffered dialysis fluid.
Area of Science:
- Nephrology
- Vascular Biology
- Biochemistry
Background:
- Ultrafiltration decline in peritoneal dialysis (PD) is linked to PD fluid-induced peritoneal angiogenesis.
- Bicarbonate-buffered PD fluid may preserve ultrafiltration better than lactate-buffered fluid, but mechanisms are unclear.
Purpose of the Study:
- To investigate the molecular mechanisms by which bicarbonate-buffered PD fluid affects endothelial cells and peritoneal angiogenesis.
- To compare the effects of bicarbonate-buffered PD fluid (BPDF) versus lactate-buffered PD fluid (LPDF) on endothelial cells and peritoneal biopsies.
Main Methods:
- Assessed angiogenic cytokine profiles, endothelial cell tube formation, and Receptor Tyrosine Kinase translocation in vitro.
- Analyzed peritoneal biopsies from children on chronic PD using histomorphometry and immunohistochemistry.
Main Results:
- BPDF significantly increased angiopoietin-1 (ANG1) mRNA and protein in endothelial cells compared to LPDF.
- BPDF reduced endothelial cell tube formation and promoted Receptor Tyrosine Kinase translocation.
- Children on BPDF showed larger peritoneal vessels and higher ANG1 expression in CD31+ endothelium compared to LPDF.
Conclusions:
- Bicarbonate buffered PD fluid promotes vascular maturation through ANG1 upregulation, offering a molecular explanation for preserved ultrafiltration.
- These findings highlight a potential therapeutic strategy for managing ultrafiltration decline in PD patients.
Background:
Ultrafiltration decline is a progressive issue for patients on chronic peritoneal dialysis (PD) and can be caused by peritoneal angiogenesis induced by PD fluids. A recent pediatric trial suggests better preservation of ultrafiltration with bicarbonate versus lactate buffered fluid; underlying molecular mechanisms are unknown.
Methods:
Angiogenic cytokine profile, tube formation capacity and Receptor Tyrosine Kinase translocation were assessed in primary human umbilical vein endothelial cells following incubation with bicarbonate (BPDF) and lactate buffered (LPDF), pH neutral PD fluid with low glucose degradation product content and lactate buffered, acidic PD fluid with high glucose degradation product content (CPDF). Peritoneal biopsies from age-, PD-vintage- and dialytic glucose exposure matched, peritonitis-free children on chronic PD underwent automated histomorphometry and immunohistochemistry.
Results:
In endothelial cells angiopoietin-1 mRNA and protein abundance increased 200% upon incubation with BPDF, but decreased by 70% with LPDF as compared to medium control; angiopoietin-2 remained unchanged. Angiopoietin-1/Angiopoietin-2 protein ratio was 15 and 3-fold increased with BPDF compared to LPDF and medium. Time-lapse microscopy with automated network analysis demonstrated less endothelial cell tube formation with BPDF compared to LPDF and CPDF incubation. Receptor Tyrosine Kinase translocated to the cell membrane in BPDF but not in LPDF or CPDF incubated endothelial cells. In children dialyzed with BPDF peritoneal vessels were larger and angiopoietin-1 abundance in CD31 positive endothelium higher compared to children treated with LPDF.
Conclusion:
Bicarbonate buffered PD fluid promotes vessel maturation via upregulation of angiopoietin-1 in vitro and in children on dialysis. Our findings suggest a molecular mechanism for the observed superior preservation of ultrafiltration capacity with bicarbonate buffered PD fluid with low glucose degradation product content.
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