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Inhibition of Toll-Like Receptor 4 Signaling Mitigates Microvascular Loss but Not Fibrosis in a Model of Ischemic Acute Kidney Injury

The development of chronic kidney disease (CKD) following an episode of acute kidney injury (AKI) is an increasingly recognized clinical problem. Inhibition of toll-like receptor 4 (TLR4) protects renal function in animal models of AKI and has become a viable therapeutic strategy in AKI. However, th...

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Autores principales: Dagher, Pierre C., Hato, Takashi, Mang, Henry E., Plotkin, Zoya, Richardson, Quentin V., Massad, Michael, Mai, Erik, Kuehl, Sarah E., Graham, Paige, Kumar, Rakesh, Sutton, Timothy A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881473/
https://www.ncbi.nlm.nih.gov/pubmed/27136544
http://dx.doi.org/10.3390/ijms17050647
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author Dagher, Pierre C.
Hato, Takashi
Mang, Henry E.
Plotkin, Zoya
Richardson, Quentin V.
Massad, Michael
Mai, Erik
Kuehl, Sarah E.
Graham, Paige
Kumar, Rakesh
Sutton, Timothy A.
author_facet Dagher, Pierre C.
Hato, Takashi
Mang, Henry E.
Plotkin, Zoya
Richardson, Quentin V.
Massad, Michael
Mai, Erik
Kuehl, Sarah E.
Graham, Paige
Kumar, Rakesh
Sutton, Timothy A.
author_sort Dagher, Pierre C.
collection PubMed
description The development of chronic kidney disease (CKD) following an episode of acute kidney injury (AKI) is an increasingly recognized clinical problem. Inhibition of toll-like receptor 4 (TLR4) protects renal function in animal models of AKI and has become a viable therapeutic strategy in AKI. However, the impact of TLR4 inhibition on the chronic sequelae of AKI is unknown. Consequently, we examined the chronic effects of TLR4 inhibition in a model of ischemic AKI. Mice with a TLR4-deletion on a C57BL/6 background and wild-type (WT) background control mice (C57BL/6) were subjected to bilateral renal artery clamping for 19 min and reperfusion for up to 6 weeks. Despite the acute protective effect of TLR4 inhibition on renal function (serum creatinine 1.6 ± 0.4 mg/dL TLR4-deletion vs. 2.8 ± 0.3 mg/dL·WT) and rates of tubular apoptosis following ischemic AKI, we found no difference in neutrophil or macrophage infiltration. Furthermore, we observed significant protection from microvascular rarefaction at six weeks following injury with TLR4-deletion, but this did not alter development of fibrosis. In conclusion, we validate the acute protective effect of TLR4 signal inhibition in AKI but demonstrate that this protective effect does not mitigate the sequential fibrogenic response in this model of ischemic AKI.
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spelling pubmed-48814732016-05-27 Inhibition of Toll-Like Receptor 4 Signaling Mitigates Microvascular Loss but Not Fibrosis in a Model of Ischemic Acute Kidney Injury Dagher, Pierre C. Hato, Takashi Mang, Henry E. Plotkin, Zoya Richardson, Quentin V. Massad, Michael Mai, Erik Kuehl, Sarah E. Graham, Paige Kumar, Rakesh Sutton, Timothy A. Int J Mol Sci Article The development of chronic kidney disease (CKD) following an episode of acute kidney injury (AKI) is an increasingly recognized clinical problem. Inhibition of toll-like receptor 4 (TLR4) protects renal function in animal models of AKI and has become a viable therapeutic strategy in AKI. However, the impact of TLR4 inhibition on the chronic sequelae of AKI is unknown. Consequently, we examined the chronic effects of TLR4 inhibition in a model of ischemic AKI. Mice with a TLR4-deletion on a C57BL/6 background and wild-type (WT) background control mice (C57BL/6) were subjected to bilateral renal artery clamping for 19 min and reperfusion for up to 6 weeks. Despite the acute protective effect of TLR4 inhibition on renal function (serum creatinine 1.6 ± 0.4 mg/dL TLR4-deletion vs. 2.8 ± 0.3 mg/dL·WT) and rates of tubular apoptosis following ischemic AKI, we found no difference in neutrophil or macrophage infiltration. Furthermore, we observed significant protection from microvascular rarefaction at six weeks following injury with TLR4-deletion, but this did not alter development of fibrosis. In conclusion, we validate the acute protective effect of TLR4 signal inhibition in AKI but demonstrate that this protective effect does not mitigate the sequential fibrogenic response in this model of ischemic AKI. MDPI 2016-04-29 /pmc/articles/PMC4881473/ /pubmed/27136544 http://dx.doi.org/10.3390/ijms17050647 Text en © 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Dagher, Pierre C.
Hato, Takashi
Mang, Henry E.
Plotkin, Zoya
Richardson, Quentin V.
Massad, Michael
Mai, Erik
Kuehl, Sarah E.
Graham, Paige
Kumar, Rakesh
Sutton, Timothy A.
Inhibition of Toll-Like Receptor 4 Signaling Mitigates Microvascular Loss but Not Fibrosis in a Model of Ischemic Acute Kidney Injury
title Inhibition of Toll-Like Receptor 4 Signaling Mitigates Microvascular Loss but Not Fibrosis in a Model of Ischemic Acute Kidney Injury
title_full Inhibition of Toll-Like Receptor 4 Signaling Mitigates Microvascular Loss but Not Fibrosis in a Model of Ischemic Acute Kidney Injury
title_fullStr Inhibition of Toll-Like Receptor 4 Signaling Mitigates Microvascular Loss but Not Fibrosis in a Model of Ischemic Acute Kidney Injury
title_full_unstemmed Inhibition of Toll-Like Receptor 4 Signaling Mitigates Microvascular Loss but Not Fibrosis in a Model of Ischemic Acute Kidney Injury
title_short Inhibition of Toll-Like Receptor 4 Signaling Mitigates Microvascular Loss but Not Fibrosis in a Model of Ischemic Acute Kidney Injury
title_sort inhibition of toll-like receptor 4 signaling mitigates microvascular loss but not fibrosis in a model of ischemic acute kidney injury
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881473/
https://www.ncbi.nlm.nih.gov/pubmed/27136544
http://dx.doi.org/10.3390/ijms17050647
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