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c-Jun Amino Terminal Kinase Signaling Promotes Aristolochic Acid-Induced Acute Kidney Injury

Aristolochic acid (AA) is a toxin that induces DNA damage in tubular epithelial cells of the kidney and is the cause of Balkan Nephropathy and Chinese Herb Nephropathy. In cultured tubular epithelial cells, AA induces a pro-fibrotic response via the c-Jun amino terminal kinase (JNK) signaling pathwa...

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Autores principales: Yang, Fan, Ozols, Elyce, Ma, Frank Y., Leong, Khai Gene, Tesch, Greg H., Jiang, Xiaoyun, Nikolic-Paterson, David J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907440/
https://www.ncbi.nlm.nih.gov/pubmed/33643061
http://dx.doi.org/10.3389/fphys.2021.599114
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author Yang, Fan
Ozols, Elyce
Ma, Frank Y.
Leong, Khai Gene
Tesch, Greg H.
Jiang, Xiaoyun
Nikolic-Paterson, David J.
author_facet Yang, Fan
Ozols, Elyce
Ma, Frank Y.
Leong, Khai Gene
Tesch, Greg H.
Jiang, Xiaoyun
Nikolic-Paterson, David J.
author_sort Yang, Fan
collection PubMed
description Aristolochic acid (AA) is a toxin that induces DNA damage in tubular epithelial cells of the kidney and is the cause of Balkan Nephropathy and Chinese Herb Nephropathy. In cultured tubular epithelial cells, AA induces a pro-fibrotic response via the c-Jun amino terminal kinase (JNK) signaling pathway. This study investigated the in vivo role of JNK signaling with a JNK inhibitor (CC-930) in mouse models of acute high dose AA-induced kidney injury (day 3) and renal fibrosis induced by chronic low dose AA exposure (day 22). CC-930 treatment inhibited JNK signaling and protected from acute AA-induced renal function impairment and severe tubular cell damage on day 3, with reduced macrophage infiltration and expression of pro-inflammatory molecules. In the chronic model, CC-930 treatment inhibited JNK signaling but did not affect AA-induced renal function impairment, tubular cell damage including the DNA damage response and induction of senescence, or renal fibrosis; despite a reduction in the macrophage pro-inflammatory response. In conclusion, JNK signaling contributes to acute high dose AA-induced tubular cell damage, presumably via an oxidative stress-dependent mechanism, but is not involved in tubular atrophy and senescence that promote chronic kidney disease caused by ongoing DNA damage in chronic low dose AA exposure.
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spelling pubmed-79074402021-02-27 c-Jun Amino Terminal Kinase Signaling Promotes Aristolochic Acid-Induced Acute Kidney Injury Yang, Fan Ozols, Elyce Ma, Frank Y. Leong, Khai Gene Tesch, Greg H. Jiang, Xiaoyun Nikolic-Paterson, David J. Front Physiol Physiology Aristolochic acid (AA) is a toxin that induces DNA damage in tubular epithelial cells of the kidney and is the cause of Balkan Nephropathy and Chinese Herb Nephropathy. In cultured tubular epithelial cells, AA induces a pro-fibrotic response via the c-Jun amino terminal kinase (JNK) signaling pathway. This study investigated the in vivo role of JNK signaling with a JNK inhibitor (CC-930) in mouse models of acute high dose AA-induced kidney injury (day 3) and renal fibrosis induced by chronic low dose AA exposure (day 22). CC-930 treatment inhibited JNK signaling and protected from acute AA-induced renal function impairment and severe tubular cell damage on day 3, with reduced macrophage infiltration and expression of pro-inflammatory molecules. In the chronic model, CC-930 treatment inhibited JNK signaling but did not affect AA-induced renal function impairment, tubular cell damage including the DNA damage response and induction of senescence, or renal fibrosis; despite a reduction in the macrophage pro-inflammatory response. In conclusion, JNK signaling contributes to acute high dose AA-induced tubular cell damage, presumably via an oxidative stress-dependent mechanism, but is not involved in tubular atrophy and senescence that promote chronic kidney disease caused by ongoing DNA damage in chronic low dose AA exposure. Frontiers Media S.A. 2021-02-12 /pmc/articles/PMC7907440/ /pubmed/33643061 http://dx.doi.org/10.3389/fphys.2021.599114 Text en Copyright © 2021 Yang, Ozols, Ma, Leong, Tesch, Jiang and Nikolic-Paterson. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Yang, Fan
Ozols, Elyce
Ma, Frank Y.
Leong, Khai Gene
Tesch, Greg H.
Jiang, Xiaoyun
Nikolic-Paterson, David J.
c-Jun Amino Terminal Kinase Signaling Promotes Aristolochic Acid-Induced Acute Kidney Injury
title c-Jun Amino Terminal Kinase Signaling Promotes Aristolochic Acid-Induced Acute Kidney Injury
title_full c-Jun Amino Terminal Kinase Signaling Promotes Aristolochic Acid-Induced Acute Kidney Injury
title_fullStr c-Jun Amino Terminal Kinase Signaling Promotes Aristolochic Acid-Induced Acute Kidney Injury
title_full_unstemmed c-Jun Amino Terminal Kinase Signaling Promotes Aristolochic Acid-Induced Acute Kidney Injury
title_short c-Jun Amino Terminal Kinase Signaling Promotes Aristolochic Acid-Induced Acute Kidney Injury
title_sort c-jun amino terminal kinase signaling promotes aristolochic acid-induced acute kidney injury
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907440/
https://www.ncbi.nlm.nih.gov/pubmed/33643061
http://dx.doi.org/10.3389/fphys.2021.599114
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