title: Antibodies to kidney endothelial cells contribute to a "leaky" glomerular barrier in patients with chronic kidney diseases.
abstract: Anti-endothelial cell antibodies (AECA) have been reported to cause endothelial dysfunction, but their clinical importance for tissue-specific endothelial cells is not clear. We hypothesized that AECA reactive with human kidney endothelial cells (HKEC) may cause renal endothelial dysfunction in patients with chronic kidney diseases. We report that a higher fraction (56%) of end-stage renal disease (ESRD) patients than healthy controls (5%) have AECA reactive against kidney endothelial cells (P <0.001). The presence of antibodies was associated with female gender (P < 0.001), systolic hypertension (P < 0.01), and elevated TNF-α (P < 0.05). These antibodies markedly decrease expression of both adherens and tight junction proteins VE-cadherin, claudin-1, and zonula occludens-1 and provoked a rapid increase in cytosolic free Ca(2+) and rearrangement of actin filaments in HKEC compared with controls. This was followed by an enhancement in protein flux and phosphorylation of VE-cadherin, events associated with augmented endothelial cell permeability. Additionally, kidney biopsies from ESRD patients with AECA but not controls demonstrated a marked decrease in adherens and tight junctions in glomerular endothelium, confirming our in vitro data. In summary, our data demonstrate a causal link between AECA and their capacity to induce alterations in glomerular vascular permeability.
authors.affiliation: Dept. of Transplantation Surgery, Laboratory for Transplantation and Regenerative Medicine, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska Science Park, Medicinaregatan 8A, Gothenburg, Sweden.
authors.forename: Nidia Maritza
authors.initials: NM
authors.lastname: Hernandez
authors.forename: Anna
authors.initials: A
authors.lastname: Casselbrant
authors.forename: Meghnad
authors.initials: M
authors.lastname: Joshi
authors.forename: Bengt R
authors.initials: BR
authors.lastname: Johansson
authors.forename: Suchitra
authors.initials: S
authors.lastname: Sumitran-Holgersson
mesh_terms: D000199:Actins / Q000378:metabolism; D022005:Adherens Junctions / Q000502:physiology*; D000328:Adult; D015703:Antigens, CD / Q000378:metabolism; D001323:Autoantibodies / Q000502:physiology*; D015820:Cadherins / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D016022:Case-Control Studies; D062445:Claudin-1; D003600:Cytosol / Q000378:metabolism; D005260:Female; D060730:Glomerular Filtration Barrier / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007676:Kidney Failure, Chronic / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D010766:Phosphorylation; D010865:Pilot Projects; D019108:Tight Junctions / Q000502:physiology*; D000099152:Cadherin 5
chemical_list: D000199:Actins; D015703:Antigens, CD; D001323:Autoantibodies; D015820:Cadherins; D002118:Calcium; D062445:Claudin-1; D007074:Immunoglobulin G; D008565:Membrane Proteins; D000099152:Cadherin 5; C568108:CLDN1 protein, human; C087589:anti-endothelial cell antibody