Renal and vascular effects of kallikrein inhibition in a model of Lonomia obliqua venom-induced acute kidney injury.
BACKGROUND:Lonomia obliqua venom is nephrotoxic and acute kidney injury (AKI) is the main cause of death among envenomed victims. Mechanism underlying L. obliqua-induced AKI involves renal hypoperfusion, inflammation, tubular necrosis and loss of glomerular filtration and tubular reabsorption capaci...
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ftdoajarticles:oai:doaj.org/article:7a24c6e74bad41be888b908acf792179 2023-05-15T15:13:55+02:00 Renal and vascular effects of kallikrein inhibition in a model of Lonomia obliqua venom-induced acute kidney injury. Markus Berger João Alfredo de Moraes Walter Orlando Beys-da-Silva Lucélia Santi Paula Barros Terraciano David Driemeier Elizabeth Obino Cirne-Lima Eduardo Pandolfi Passos Maria Aparecida Ribeiro Vieira Thereza Christina Barja-Fidalgo Jorge Almeida Guimarães 2019-02-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0007197 https://doaj.org/article/7a24c6e74bad41be888b908acf792179 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC6392336?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0007197 https://doaj.org/article/7a24c6e74bad41be888b908acf792179 PLoS Neglected Tropical Diseases, Vol 13, Iss 2, p e0007197 (2019) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2019 ftdoajarticles https://doi.org/10.1371/journal.pntd.0007197 2022-12-31T13:32:59Z BACKGROUND:Lonomia obliqua venom is nephrotoxic and acute kidney injury (AKI) is the main cause of death among envenomed victims. Mechanism underlying L. obliqua-induced AKI involves renal hypoperfusion, inflammation, tubular necrosis and loss of glomerular filtration and tubular reabsorption capacities. In the present study, we aimed to investigate the contribution of kallikrein to the hemodynamic instability, inflammation and consequent renal and vascular impairment. METHODOLOGY/PRINCIPAL FINDINGS:Addition of L. obliqua venom to purified prekallikrein and human plasma in vitro or to vascular smooth muscle cells (VSMC) in culture, was able to generate kallikrein in a dose-dependent manner. Injected in rats, the venom induced AKI and increased kallikrein levels in plasma and kidney. Kallikrein inhibition by aprotinin prevented glomerular injury and the decrease in glomerular filtration rate, restoring fluid and electrolyte homeostasis. The mechanism underlying these effects was associated to lowering renal inflammation, with decrease in pro-inflammatory cytokines and matrix metalloproteinase expression, reduced tubular degeneration, and protection against oxidative stress. Supporting the key role of kallikrein, we demonstrated that aprotinin inhibited effects directly associated with vascular injury, such as the generation of intracellular reactive oxygen species (ROS) and migration of VSMC induced by L. obliqua venom or by diluted plasma obtained from envenomed rats. In addition, kallikrein inhibition also ameliorated venom-induced blood incoagulability and decreased kidney tissue factor expression. CONCLUSIONS/SIGNIFICANCE:These data indicated that kallikrein and consequently kinin release have a key role in kidney injury and vascular remodeling. Thus, blocking kallikrein may be a therapeutic alternative to control the progression of venom-induced AKI and vascular disturbances. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 13 2 e0007197 |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Markus Berger João Alfredo de Moraes Walter Orlando Beys-da-Silva Lucélia Santi Paula Barros Terraciano David Driemeier Elizabeth Obino Cirne-Lima Eduardo Pandolfi Passos Maria Aparecida Ribeiro Vieira Thereza Christina Barja-Fidalgo Jorge Almeida Guimarães Renal and vascular effects of kallikrein inhibition in a model of Lonomia obliqua venom-induced acute kidney injury. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
BACKGROUND:Lonomia obliqua venom is nephrotoxic and acute kidney injury (AKI) is the main cause of death among envenomed victims. Mechanism underlying L. obliqua-induced AKI involves renal hypoperfusion, inflammation, tubular necrosis and loss of glomerular filtration and tubular reabsorption capacities. In the present study, we aimed to investigate the contribution of kallikrein to the hemodynamic instability, inflammation and consequent renal and vascular impairment. METHODOLOGY/PRINCIPAL FINDINGS:Addition of L. obliqua venom to purified prekallikrein and human plasma in vitro or to vascular smooth muscle cells (VSMC) in culture, was able to generate kallikrein in a dose-dependent manner. Injected in rats, the venom induced AKI and increased kallikrein levels in plasma and kidney. Kallikrein inhibition by aprotinin prevented glomerular injury and the decrease in glomerular filtration rate, restoring fluid and electrolyte homeostasis. The mechanism underlying these effects was associated to lowering renal inflammation, with decrease in pro-inflammatory cytokines and matrix metalloproteinase expression, reduced tubular degeneration, and protection against oxidative stress. Supporting the key role of kallikrein, we demonstrated that aprotinin inhibited effects directly associated with vascular injury, such as the generation of intracellular reactive oxygen species (ROS) and migration of VSMC induced by L. obliqua venom or by diluted plasma obtained from envenomed rats. In addition, kallikrein inhibition also ameliorated venom-induced blood incoagulability and decreased kidney tissue factor expression. CONCLUSIONS/SIGNIFICANCE:These data indicated that kallikrein and consequently kinin release have a key role in kidney injury and vascular remodeling. Thus, blocking kallikrein may be a therapeutic alternative to control the progression of venom-induced AKI and vascular disturbances. |
format |
Article in Journal/Newspaper |
author |
Markus Berger João Alfredo de Moraes Walter Orlando Beys-da-Silva Lucélia Santi Paula Barros Terraciano David Driemeier Elizabeth Obino Cirne-Lima Eduardo Pandolfi Passos Maria Aparecida Ribeiro Vieira Thereza Christina Barja-Fidalgo Jorge Almeida Guimarães |
author_facet |
Markus Berger João Alfredo de Moraes Walter Orlando Beys-da-Silva Lucélia Santi Paula Barros Terraciano David Driemeier Elizabeth Obino Cirne-Lima Eduardo Pandolfi Passos Maria Aparecida Ribeiro Vieira Thereza Christina Barja-Fidalgo Jorge Almeida Guimarães |
author_sort |
Markus Berger |
title |
Renal and vascular effects of kallikrein inhibition in a model of Lonomia obliqua venom-induced acute kidney injury. |
title_short |
Renal and vascular effects of kallikrein inhibition in a model of Lonomia obliqua venom-induced acute kidney injury. |
title_full |
Renal and vascular effects of kallikrein inhibition in a model of Lonomia obliqua venom-induced acute kidney injury. |
title_fullStr |
Renal and vascular effects of kallikrein inhibition in a model of Lonomia obliqua venom-induced acute kidney injury. |
title_full_unstemmed |
Renal and vascular effects of kallikrein inhibition in a model of Lonomia obliqua venom-induced acute kidney injury. |
title_sort |
renal and vascular effects of kallikrein inhibition in a model of lonomia obliqua venom-induced acute kidney injury. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2019 |
url |
https://doi.org/10.1371/journal.pntd.0007197 https://doaj.org/article/7a24c6e74bad41be888b908acf792179 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 13, Iss 2, p e0007197 (2019) |
op_relation |
http://europepmc.org/articles/PMC6392336?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0007197 https://doaj.org/article/7a24c6e74bad41be888b908acf792179 |
op_doi |
https://doi.org/10.1371/journal.pntd.0007197 |
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PLOS Neglected Tropical Diseases |
container_volume |
13 |
container_issue |
2 |
container_start_page |
e0007197 |
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1766344420750262272 |