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Abrogation of plasminogen activator inhibitor-1-vitronectin interaction ameliorates acute kidney injury in murine endotoxemia

Sepsis-induced acute kidney injury (AKI) contributes to the high mortality and morbidity in patients. Although the pathogenesis of AKI during sepsis is poorly understood, it is well accepted that plasminogen activator inhibitor-1 (PAI-1) and vitronectin (Vn) are involved in AKI. However, the functio...

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Published in:PloS one 2015-03, Vol.10 (3), p.e0120728
Main Authors: Gupta, Kamlesh K, Donahue, Deborah L, Sandoval-Cooper, Mayra J, Castellino, Francis J, Ploplis, Victoria A
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Donahue, Deborah L
Sandoval-Cooper, Mayra J
Castellino, Francis J
Ploplis, Victoria A
description Sepsis-induced acute kidney injury (AKI) contributes to the high mortality and morbidity in patients. Although the pathogenesis of AKI during sepsis is poorly understood, it is well accepted that plasminogen activator inhibitor-1 (PAI-1) and vitronectin (Vn) are involved in AKI. However, the functional cooperation between PAI-1 and Vn in septic AKI has not been completely elucidated. To address this issue, mice were utilized lacking either PAI-1 (PAI-1-/-) or expressing a PAI-1-mutant (PAI-1R101A/Q123K) in which the interaction between PAI-1 and Vn is abrogated, while other functions of PAI-1 are retained. It was found that both PAI-1-/- and PAI-1R101A/Q123K mice are associated with decreased renal dysfunction, apoptosis, inflammation, and ERK activation as compared to wild-type (WT) mice after LPS challenge. Also, PAI-1-/- mice showed attenuated fibrin deposition in the kidneys. Furthermore, a lack of PAI-1 or PAI-1-Vn interaction was found to be associated with an increase in activated Protein C (aPC) in plasma. These results demonstrate that PAI-1, through its interaction with Vn, exerts multiple deleterious mechanisms to induce AKI. Therefore, targeting of the PAI-1-Vn interaction in kidney represents an appealing therapeutic strategy for the treatment of septic AKI by not only altering the fibrinolytic capacity but also regulating PC activity.
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Although the pathogenesis of AKI during sepsis is poorly understood, it is well accepted that plasminogen activator inhibitor-1 (PAI-1) and vitronectin (Vn) are involved in AKI. However, the functional cooperation between PAI-1 and Vn in septic AKI has not been completely elucidated. To address this issue, mice were utilized lacking either PAI-1 (PAI-1-/-) or expressing a PAI-1-mutant (PAI-1R101A/Q123K) in which the interaction between PAI-1 and Vn is abrogated, while other functions of PAI-1 are retained. It was found that both PAI-1-/- and PAI-1R101A/Q123K mice are associated with decreased renal dysfunction, apoptosis, inflammation, and ERK activation as compared to wild-type (WT) mice after LPS challenge. Also, PAI-1-/- mice showed attenuated fibrin deposition in the kidneys. Furthermore, a lack of PAI-1 or PAI-1-Vn interaction was found to be associated with an increase in activated Protein C (aPC) in plasma. These results demonstrate that PAI-1, through its interaction with Vn, exerts multiple deleterious mechanisms to induce AKI. 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These results demonstrate that PAI-1, through its interaction with Vn, exerts multiple deleterious mechanisms to induce AKI. Therefore, targeting of the PAI-1-Vn interaction in kidney represents an appealing therapeutic strategy for the treatment of septic AKI by not only altering the fibrinolytic capacity but also regulating PC activity.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25799354</pmid><doi>10.1371/journal.pone.0120728</doi><oa>free_for_read</oa></addata></record>
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subjects Activated protein C
Acute Kidney Injury - etiology
Acute Kidney Injury - metabolism
Acute Kidney Injury - pathology
Animals
Apoptosis
Biochemistry
Cytokines - metabolism
Disease Models, Animal
Endotoxemia
Endotoxemia - complications
Fibrin
Fibrin - metabolism
Gene expression
Health aspects
Infection
Inflammation Mediators - metabolism
Inhibitors
Intercellular Adhesion Molecule-1 - genetics
Intercellular Adhesion Molecule-1 - metabolism
Kidneys
Lipopolysaccharides
Lipopolysaccharides - adverse effects
Male
MAP Kinase Signaling System
Mice
Mice, Knockout
Morbidity
Mortality
Neutrophil Infiltration
Pathogenesis
Plasminogen Activator Inhibitor 1 - genetics
Plasminogen Activator Inhibitor 1 - metabolism
Plasminogen activator inhibitors
Protein Binding
Proteins
Renal function
Rodents
Sepsis
Studies
TNF inhibitors
Tumor necrosis factor-TNF
Vitronectin
Vitronectin - metabolism
title Abrogation of plasminogen activator inhibitor-1-vitronectin interaction ameliorates acute kidney injury in murine endotoxemia
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-30T00%3A03%3A39IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Abrogation%20of%20plasminogen%20activator%20inhibitor-1-vitronectin%20interaction%20ameliorates%20acute%20kidney%20injury%20in%20murine%20endotoxemia&rft.jtitle=PloS%20one&rft.au=Gupta,%20Kamlesh%20K&rft.date=2015-03-23&rft.volume=10&rft.issue=3&rft.spage=e0120728&rft.pages=e0120728-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0120728&rft_dat=%3Cgale_plos_%3EA422548270%3C/gale_plos_%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c758t-6d5154f67c0d074ed204a53643b16742ddc4262bb5b74f58ee0899195bd223fe3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=1667181226&rft_id=info:pmid/25799354&rft_galeid=A422548270&rfr_iscdi=true