Abstract
Peritoneal dialysis (PD) is a form of renal replacement treatment, which employs the peritoneal membrane (PM) to eliminate toxins that cannot be removed by the kidney. The procedure itself, however, contributes to the loss of the PM ultrafiltration capacity (UFC), leading consequently to the technique malfunction. β-blockers have been considered deleterious for PM due to their association with loss of UFC and induction of fibrosis. Herein we analyzed the effects of Nebivolol, a new generation of β1-blocker, on PM alterations induced by PD fluids (PDF).In vitro: We found that mesothelial cells (MCs) express β1-adrenergic receptor. MCs were treated with TGF-β to induce mesothelial-to-mesenchymal transition (MMT) and co-treated with Nebivolol. Nebivolol reversed the TGF-β effects, decreasing extracellular matrix synthesis, and improved the fibrinolytic capacity, decreasing plasminogen activator inhibitor-1 (PAI-1) and increasing tissue-type plasminogen activator (tPA) supernatant levels. Moreover, Nebivolol partially inhibited MMT and decreased vascular endothelial growth factor (VEGF) and IL-6 levels in supernatants.In vivo: Twenty-one C57BL/6 mice were divided into 3 groups. Control group carried a catheter without PDF infusion. Study group received intraperitoneally PDF and oral Nebivolol during 30 days. PDF group received PDF alone. Nebivolol maintained the UFC and reduced PM thickness, MMT and angiogenesis promoted by PDF. It also improved the fibrinolytic capacity in PD effluents decreasing PAI-1 and IL-8 and increased tPA levels.Conclusion: Nebivolol protects PM from PDF-induced damage, promoting anti-fibrotic, anti-angiogenic, anti-inflammatory and pro-fibrinolytic effects.
Highlights
Peritoneal dialysis (PD) is a renal replacement therapy commonly used around the world
We demonstrate for the first time that Human omentum derived mesothelial cells (HOMCs) show β1-adrenergic receptor (β1-AR) (Figure 1A, 1B) and that Nebivolol (10 nM) decreased its expression
Recent publications show that β1-AR blockade is generally associated with anti-fibrotic and anti-angiogenic effects [18, 19]
Summary
Peritoneal dialysis (PD) is a renal replacement therapy commonly used around the world. Ultrafiltration failure (UFF) along with acute peritonitis are major causes of the technique dropout [1]. The factors associated to PM failure include chronic and acute peritoneal inflammation caused by bacteria, www.impactjournals.com/oncotarget glucose degradation products, advanced glycation end-products, acidic pH from PD fluids (PDF), and hemoperitoneum [2, 3]. Activated inflammatory cells subsequently drive fibrotic and pro-angiogenic factors and stimulates mesothelial cells (MCs) to start transdifferentiation. This process is so-called mesothelial-tomesenchymal transition (MMT), in which MCs acquire a fibroblast-like phenotype [4], lose their basoapical and basolateral polarity and acquire migratory capacity towards the submesothelium, where they synthesize extracellular matrix (ECM) and vascular endothelial growth factor (VEGF), contributing to PM structural damage. Numerous efforts have been made to improve the PDF biocompatibility and to investigate drugs capable of neutralizing the PM damage [3]
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