Uremia Impacts VE-Cadherin and ZO-1 Expression in Human Endothelial Cell-to-Cell Junctions
Rayana A. P. Maciel,
Regiane S. Cunha,
Valentina Busato,
Célia R. C. Franco,
Paulo C. Gregório,
Carla J. R. Dolenga,
Lia S. Nakao,
Ziad A. Massy,
Agnès Boullier,
Roberto Pecoits-Filho,
Andréa E. M. Stinghen
Affiliations
Rayana A. P. Maciel
Experimental Nephrology Laboratory, Basic Pathology Department, Universidade Federal do Paraná, Curitiba 80050-540, Brazil
Regiane S. Cunha
Experimental Nephrology Laboratory, Basic Pathology Department, Universidade Federal do Paraná, Curitiba 80050-540, Brazil
Valentina Busato
Experimental Nephrology Laboratory, Basic Pathology Department, Universidade Federal do Paraná, Curitiba 80050-540, Brazil
Célia R. C. Franco
Cell Biology Department, Universidade Federal do Paraná, Curitiba 80050-540, Brazil
Paulo C. Gregório
Experimental Nephrology Laboratory, Basic Pathology Department, Universidade Federal do Paraná, Curitiba 80050-540, Brazil
Carla J. R. Dolenga
Basic Pathology Department, Universidade Federal do Paraná, Curitiba 80050-540, Brazil
Lia S. Nakao
Basic Pathology Department, Universidade Federal do Paraná, Curitiba 80050-540, Brazil
Ziad A. Massy
Division of Nephrology, Ambroise Paré University Hospital, APHP, Boulogne-Billancourt, 92100 Paris, France and Inserm U1018, Team 5, CESP, UVSQ, Paris-Saclay University, 94800 Villejuif, France
Agnès Boullier
Universitè de Picardie Jules Verne, MP3CV and CHU d’Amiens, 80025 Amiens, France
Roberto Pecoits-Filho
Pontifícia Universidade Católica do Paraná, School of Medicine, Curitiba 80215-901, Brazil
Andréa E. M. Stinghen
Experimental Nephrology Laboratory, Basic Pathology Department, Universidade Federal do Paraná, Curitiba 80050-540, Brazil
Endothelial dysfunction in uremia can result in cell-to-cell junction loss and increased permeability, contributing to cardiovascular diseases (CVD) development. This study evaluated the impact of the uremic milieu on endothelial morphology and cell junction’s proteins. We evaluated (i) serum levels of inflammatory biomarkers in a cohort of chronic kidney disease (CKD) patients and the expression of VE-cadherin and Zonula Occludens-1 (ZO-1) junction proteins on endothelial cells (ECs) of arteries removed from CKD patients during renal transplant; (ii) ECs morphology in vitro under different uremic conditions, and (iii) the impact of uremic toxins p-cresyl sulfate (PCS), indoxyl sulfate (IS), and inorganic phosphate (Pi) as well as of total uremic serum on VE-cadherin and ZO-1 gene and protein expression in cultured ECs. We found that the uremic arteries had lost their intact and continuous endothelial morphology, with a reduction in VE-cadherin and ZO-1 expression. In cultured ECs, both VE-cadherin and ZO-1 protein expression decreased, mainly after exposure to Pi and uremic serum groups. VE-cadherin mRNA expression was reduced while ZO-1 was increased after exposure to PCS, IS, Pi, and uremic serum. Our findings show that uremia alters cell-to-cell junctions leading to an increased endothelial damage. This gives a new perspective regarding the pathophysiological role of uremia in intercellular junctions and opens new avenues to improve cardiovascular outcomes in CKD patients.
