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Renal Impairment with Sublethal Tubular Cell Injury in a Chronic Liver Disease Mouse Model
The pathogenesis of renal impairment in chronic liver diseases (CLDs) has been primarily studied in the advanced stages of hepatic injury. Meanwhile, the pathology of renal impairment in the early phase of CLDs is poorly understood, and animal models to elucidate its mechanisms are needed. Thus, we...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4713438/ https://www.ncbi.nlm.nih.gov/pubmed/26752420 http://dx.doi.org/10.1371/journal.pone.0146871 |
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author | Ishida, Tokiko Kotani, Hirokazu Miyao, Masashi Kawai, Chihiro Jemail, Leila Abiru, Hitoshi Tamaki, Keiji |
author_facet | Ishida, Tokiko Kotani, Hirokazu Miyao, Masashi Kawai, Chihiro Jemail, Leila Abiru, Hitoshi Tamaki, Keiji |
author_sort | Ishida, Tokiko |
collection | PubMed |
description | The pathogenesis of renal impairment in chronic liver diseases (CLDs) has been primarily studied in the advanced stages of hepatic injury. Meanwhile, the pathology of renal impairment in the early phase of CLDs is poorly understood, and animal models to elucidate its mechanisms are needed. Thus, we investigated whether an existing mouse model of CLD induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) shows renal impairment in the early phase. Renal injury markers, renal histology (including immunohistochemistry for tubular injury markers and transmission electron microscopy), autophagy, and oxidative stress were studied longitudinally in DDC- and standard diet–fed BALB/c mice. Slight but significant renal dysfunction was evident in DDC-fed mice from the early phase. Meanwhile, histological examinations of the kidneys with routine light microscopy did not show definitive morphological findings, and electron microscopic analyses were required to detect limited injuries such as loss of brush border microvilli and mitochondrial deformities. Limited injuries have been recently designated as sublethal tubular cell injury. As humans with renal impairment, either with or without CLD, often show almost normal tubules, sublethal injury has been of particular interest. In this study, the injuries were associated with mitochondrial aberrations and oxidative stress, a possible mechanism for sublethal injury. Intriguingly, two defense mechanisms were associated with this injury that prevent it from progressing to apparent cell death: autophagy and single-cell extrusion with regeneration. Furthermore, the renal impairment of this model progressed to chronic kidney disease with interstitial fibrosis after long-term DDC feeding. These findings indicated that DDC induces renal impairment with sublethal tubular cell injury from the early phase, leading to chronic kidney disease. Importantly, this CLD mouse model could be useful for studying the pathophysiological mechanisms of sublethal tubular cell injury. |
format | Online Article Text |
id | pubmed-4713438 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-47134382016-01-26 Renal Impairment with Sublethal Tubular Cell Injury in a Chronic Liver Disease Mouse Model Ishida, Tokiko Kotani, Hirokazu Miyao, Masashi Kawai, Chihiro Jemail, Leila Abiru, Hitoshi Tamaki, Keiji PLoS One Research Article The pathogenesis of renal impairment in chronic liver diseases (CLDs) has been primarily studied in the advanced stages of hepatic injury. Meanwhile, the pathology of renal impairment in the early phase of CLDs is poorly understood, and animal models to elucidate its mechanisms are needed. Thus, we investigated whether an existing mouse model of CLD induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) shows renal impairment in the early phase. Renal injury markers, renal histology (including immunohistochemistry for tubular injury markers and transmission electron microscopy), autophagy, and oxidative stress were studied longitudinally in DDC- and standard diet–fed BALB/c mice. Slight but significant renal dysfunction was evident in DDC-fed mice from the early phase. Meanwhile, histological examinations of the kidneys with routine light microscopy did not show definitive morphological findings, and electron microscopic analyses were required to detect limited injuries such as loss of brush border microvilli and mitochondrial deformities. Limited injuries have been recently designated as sublethal tubular cell injury. As humans with renal impairment, either with or without CLD, often show almost normal tubules, sublethal injury has been of particular interest. In this study, the injuries were associated with mitochondrial aberrations and oxidative stress, a possible mechanism for sublethal injury. Intriguingly, two defense mechanisms were associated with this injury that prevent it from progressing to apparent cell death: autophagy and single-cell extrusion with regeneration. Furthermore, the renal impairment of this model progressed to chronic kidney disease with interstitial fibrosis after long-term DDC feeding. These findings indicated that DDC induces renal impairment with sublethal tubular cell injury from the early phase, leading to chronic kidney disease. Importantly, this CLD mouse model could be useful for studying the pathophysiological mechanisms of sublethal tubular cell injury. Public Library of Science 2016-01-11 /pmc/articles/PMC4713438/ /pubmed/26752420 http://dx.doi.org/10.1371/journal.pone.0146871 Text en © 2016 Ishida et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Ishida, Tokiko Kotani, Hirokazu Miyao, Masashi Kawai, Chihiro Jemail, Leila Abiru, Hitoshi Tamaki, Keiji Renal Impairment with Sublethal Tubular Cell Injury in a Chronic Liver Disease Mouse Model |
title | Renal Impairment with Sublethal Tubular Cell Injury in a Chronic Liver Disease Mouse Model |
title_full | Renal Impairment with Sublethal Tubular Cell Injury in a Chronic Liver Disease Mouse Model |
title_fullStr | Renal Impairment with Sublethal Tubular Cell Injury in a Chronic Liver Disease Mouse Model |
title_full_unstemmed | Renal Impairment with Sublethal Tubular Cell Injury in a Chronic Liver Disease Mouse Model |
title_short | Renal Impairment with Sublethal Tubular Cell Injury in a Chronic Liver Disease Mouse Model |
title_sort | renal impairment with sublethal tubular cell injury in a chronic liver disease mouse model |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4713438/ https://www.ncbi.nlm.nih.gov/pubmed/26752420 http://dx.doi.org/10.1371/journal.pone.0146871 |
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