Proteome-Wide Differential Effects of Peritoneal Dialysis Fluid Properties in an In Vitro Human Endothelial Cell Model

Abstract

To replace kidney function, peritoneal dialysis (PD) utilizes hyperosmotic PD fluids with specific physico-chemical properties. Their composition induces progressive damage of the peritoneum, leading to vasculopathies, decline of membrane function, and PD technique failure. Clinically used PD fluids differ in their composition but still remain bioincompatible. We mapped the molecular pathomechanisms in human endothelial cells induced by the different characteristics of widely used PD fluids by proteomics. Of 7894 identified proteins, 3871 were regulated at least by 1 and 49 by all tested PD fluids. The latter subset was enriched for cell junction-associated proteins. The different PD fluids individually perturbed proteins commonly related to cell stress, survival, and immune function pathways. Modeling two major bioincompatibility factors of PD fluids, acidosis, and glucose degradation products (GDPs) revealed distinct effects on endothelial cell function and regulation of cellular stress responses. Proteins and pathways most strongly affected were members of the oxidative stress response. Addition of the antioxidant and cytoprotective additive, alanyl-glutamine (AlaGln), to PD fluids led to upregulation of thioredoxin reductase-1, an antioxidant protein, potentially explaining the cytoprotective effect of AlaGln. In conclusion, we mapped out the molecular response of endothelial cells to PD fluids, and provided new evidence for their specific pathomechanisms, crucial for improvement of PD therapies.

Maßnahmen zum peritonealen Langzeiterhalt

“…In den letzten Jahren konnten durch große Omics-Analysen weitere positive Ergebnisse zu AlaGln als PDF-Zusatz gezeigt werden [39][40][41][42][43][44]. Proteom-und Metabolomanalysen demonstrierten, dass AlaGln den PDF-induzierte Pathomechanismen der Vaskulopathie entgegenwirken kann oder als Antioxidans wirksam ist [42,44]. Darüber hinaus wirkt AlaGln nicht nur protektiv auf peritoneale Zellen, sondern gleichzeitig antiinflammatorisch [44,45].…”

Hyperglycolysis in endothelial cells drives endothelial injury and microvascular alterations in peritoneal dialysis

“…6 Microvascular alterations in PD, as defined by increases in microvessel density, vascular permeability and monocyte transendothelial migration, presumably result from endothelial cell (EC) proliferation, inflammation or injury. [7][8][9][10] However, the underlying mechanisms of EC dysfunction in PD are poorly defined. ECs, which line the inner vascular wall, act as the primary barrier for solute transport across the vessel wall, and play an essential role in regulating angiogenesis, vascular integrity and monocyte extravasation.…”

“…Despite decades of intense research, less is known about the cues that induce EC dysfunction in PD. 7 Current vascular normalization strategies focus mainly on targeting angiogenic growth factors, including the vascular endothelial growth factor (VEGF). 16,17 But blockade of one growth factor would lead to compensatory upregulation of others, which could stimulate vascular changes again.…”

“…Extended exposure of the peritoneum to glucose‐based PD fluids induces progressive mesothelial cell loss, submesothelial fibrosis and microvascular alterations, culminating in ultrafiltration failure 6 . Microvascular alterations in PD, as defined by increases in microvessel density, vascular permeability and monocyte transendothelial migration, presumably result from endothelial cell (EC) proliferation, inflammation or injury 7–10 . However, the underlying mechanisms of EC dysfunction in PD are poorly defined.…”

“…Not unexpectedly, microvascular alterations in PD accelerate solute transfer, 13,14 facilitate peritoneal inflammation with fibrotic consequences, 15 and thus contribute to loss of PD efficacy. Despite decades of intense research, less is known about the cues that induce EC dysfunction in PD 7 . Current vascular normalization strategies focus mainly on targeting angiogenic growth factors, including the vascular endothelial growth factor (VEGF) 16,17 .…”