Nebivolol, a β1-adrenergic blocker, protects from peritoneal membrane damage induced during peritoneal dialysis.
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.


CONCLUSIONS
Nebivolol protects PM from PDF-induced damage, promoting anti-fibrotic, anti-angiogenic, anti-inflammatory and pro-fibrinolytic effects.
Immunology and Cellular Biology Department, Molecular Biology Centre Severo Ochoa, Madrid, Spain.
Georgios
G
Liappas
Immunology and Cellular Biology Department, Molecular Biology Centre Severo Ochoa, Madrid, Spain.
Guadalupe
G
González-Mateo
Nephrology Department, University of Sao Paulo, School of Medicine, Sao Paulo, Brazil.
Anna Rita
AR
Aguirre
Nephrology Department, University of Sao Paulo, School of Medicine, Sao Paulo, Brazil.
Hugo
H
Abensur
Molecular Biology Unit and Nephrology Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain.
Patricia
P
Albar-Vizcaino
Nephrology Department, Fundación Jiménez-Díaz, Instituto de Investigación Sanitaria, Madrid, Spain.
Emilio González
EG
Parra
Immunology and Cellular Biology Department, Molecular Biology Centre Severo Ochoa, Madrid, Spain.
Pilar
P
Sandoval
Molecular Biology Unit and Nephrology Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain.
Laura García
LG
Ramírez
Nephrology Department, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid, Spain.
Gloria
G
Del Peso
Cardiology Department, Clínica La Luz, Madrid, Spain.
Juan Manuel
JM
Acedo
Nephrology Department, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid, Spain.
María A
MA
Bajo
Nephrology Department, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid, Spain.
Rafael
R
Selgas
Molecular Biology Unit and Nephrology Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain.
José A
JA
Sánchez Tomero
Immunology and Cellular Biology Department, Molecular Biology Centre Severo Ochoa, Madrid, Spain.
Manuel
M
López-Cabrera
Molecular Biology Unit and Nephrology Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain.
Abelardo
A
Aguilera
D058665:Adrenergic beta-1 Receptor Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002478:Cells, Cultured; D015314:Dialysis Solutions / Q000009:adverse effects*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D005342:Fibrinolysis / Q000187:drug effects; D005355:Fibrosis; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000068577:Nebivolol / Q000494:pharmacology* / Q000627:therapeutic use; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000188:drug therapy; D010530:Peritoneal Dialysis / Q000009:adverse effects*; D010537:Peritoneum / Q000166:cytology / Q000187:drug effects* / Q000473:pathology*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D058258:Serpin E2 / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D058665:Adrenergic beta-1 Receptor Agonists; D015314:Dialysis Solutions; D016209:Interleukin-8; D017395:Plasminogen Activator Inhibitor 1; D018342:Receptors, Adrenergic, beta-1; C051321:SERPINE1 protein, human; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D016212:Transforming Growth Factor beta; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068577:Nebivolol; C067262:PLAT protein, human; D010959:Tissue Plasminogen Activator
Pathology Section; nebivolol; peritoneal dialysis; peritoneal dialysis liquids; type-I peritoneal membrane failure; β-adrenergic receptor