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Pharmacological Inhibition of Fatty Acid-Binding Protein 4 (FABP4) Protects Against Rhabdomyolysis-Induced Acute Kidney Injury

Acute kidney injury (AKI) is a common and potentially life-threatening complication. Studies confirmed that circulating FABP4 depended on renal function of AKI patients. In our previous study, FABP4 was involved in the pathogenesis of I/R-induced AKI. However, the function of FABP4 in rhabdomyolysis...

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Autores principales: Huang, Rongshuang, Shi, Min, Guo, Fan, Feng, Yuying, Feng, Yanhuan, Liu, Jing, Li, Lingzhi, Liang, Yan, Xiang, Jin, Lei, Song, Ma, Liang, Fu, Ping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092613/
https://www.ncbi.nlm.nih.gov/pubmed/30135658
http://dx.doi.org/10.3389/fphar.2018.00917
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author Huang, Rongshuang
Shi, Min
Guo, Fan
Feng, Yuying
Feng, Yanhuan
Liu, Jing
Li, Lingzhi
Liang, Yan
Xiang, Jin
Lei, Song
Ma, Liang
Fu, Ping
author_facet Huang, Rongshuang
Shi, Min
Guo, Fan
Feng, Yuying
Feng, Yanhuan
Liu, Jing
Li, Lingzhi
Liang, Yan
Xiang, Jin
Lei, Song
Ma, Liang
Fu, Ping
author_sort Huang, Rongshuang
collection PubMed
description Acute kidney injury (AKI) is a common and potentially life-threatening complication. Studies confirmed that circulating FABP4 depended on renal function of AKI patients. In our previous study, FABP4 was involved in the pathogenesis of I/R-induced AKI. However, the function of FABP4 in rhabdomyolysis-induced AKI remained poorly understood. In the study, we further investigated the effect of FABP4 in a murine model of glycerol injection-induced rhabdomyolysis. Following glycerol injection, the mice developed severe AKI as indicated by acute renal dysfunction and histologic changes, companied by the increased FABP4 expression in the cytoplasm of tubular epithelial cells. Pharmacological inhibition of FABP4 by a highly selective inhibitor BMS309403 significantly reduced serum creatinine level, proinflammatory cytokine mRNA expression of tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein 1 as well as attenuated renal tubular damage in glycerol-injured kidneys. Oral administration of FABP4 inhibitor also resulted in a significant attenuation of ER stress indicated by transmission electron microscope analysis and its maker proteins expression of GRP78, CHOP, p-perk, and ATF4 in kidneys of AKI. Furthermore, BMS309403 could attenuate myoglobin-induced ER stress and inflammation in renal proximal tubular epithelial cell line (HK-2). Overall, these data highlighted that renal protection of selective FABP4 inhibitor was substantiated by the reduction of ER stress and inflammation in tubular epithelial cells of rhabdomyolysis-induced injured kidneys and suggested that the inhibition of FABP4 might be a promising therapeutic strategy for AKI treatment.
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spelling pubmed-60926132018-08-22 Pharmacological Inhibition of Fatty Acid-Binding Protein 4 (FABP4) Protects Against Rhabdomyolysis-Induced Acute Kidney Injury Huang, Rongshuang Shi, Min Guo, Fan Feng, Yuying Feng, Yanhuan Liu, Jing Li, Lingzhi Liang, Yan Xiang, Jin Lei, Song Ma, Liang Fu, Ping Front Pharmacol Pharmacology Acute kidney injury (AKI) is a common and potentially life-threatening complication. Studies confirmed that circulating FABP4 depended on renal function of AKI patients. In our previous study, FABP4 was involved in the pathogenesis of I/R-induced AKI. However, the function of FABP4 in rhabdomyolysis-induced AKI remained poorly understood. In the study, we further investigated the effect of FABP4 in a murine model of glycerol injection-induced rhabdomyolysis. Following glycerol injection, the mice developed severe AKI as indicated by acute renal dysfunction and histologic changes, companied by the increased FABP4 expression in the cytoplasm of tubular epithelial cells. Pharmacological inhibition of FABP4 by a highly selective inhibitor BMS309403 significantly reduced serum creatinine level, proinflammatory cytokine mRNA expression of tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein 1 as well as attenuated renal tubular damage in glycerol-injured kidneys. Oral administration of FABP4 inhibitor also resulted in a significant attenuation of ER stress indicated by transmission electron microscope analysis and its maker proteins expression of GRP78, CHOP, p-perk, and ATF4 in kidneys of AKI. Furthermore, BMS309403 could attenuate myoglobin-induced ER stress and inflammation in renal proximal tubular epithelial cell line (HK-2). Overall, these data highlighted that renal protection of selective FABP4 inhibitor was substantiated by the reduction of ER stress and inflammation in tubular epithelial cells of rhabdomyolysis-induced injured kidneys and suggested that the inhibition of FABP4 might be a promising therapeutic strategy for AKI treatment. Frontiers Media S.A. 2018-08-08 /pmc/articles/PMC6092613/ /pubmed/30135658 http://dx.doi.org/10.3389/fphar.2018.00917 Text en Copyright © 2018 Huang, Shi, Guo, Feng, Feng, Liu, Li, Liang, Xiang, Lei, Ma and Fu. http://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 Pharmacology
Huang, Rongshuang
Shi, Min
Guo, Fan
Feng, Yuying
Feng, Yanhuan
Liu, Jing
Li, Lingzhi
Liang, Yan
Xiang, Jin
Lei, Song
Ma, Liang
Fu, Ping
Pharmacological Inhibition of Fatty Acid-Binding Protein 4 (FABP4) Protects Against Rhabdomyolysis-Induced Acute Kidney Injury
title Pharmacological Inhibition of Fatty Acid-Binding Protein 4 (FABP4) Protects Against Rhabdomyolysis-Induced Acute Kidney Injury
title_full Pharmacological Inhibition of Fatty Acid-Binding Protein 4 (FABP4) Protects Against Rhabdomyolysis-Induced Acute Kidney Injury
title_fullStr Pharmacological Inhibition of Fatty Acid-Binding Protein 4 (FABP4) Protects Against Rhabdomyolysis-Induced Acute Kidney Injury
title_full_unstemmed Pharmacological Inhibition of Fatty Acid-Binding Protein 4 (FABP4) Protects Against Rhabdomyolysis-Induced Acute Kidney Injury
title_short Pharmacological Inhibition of Fatty Acid-Binding Protein 4 (FABP4) Protects Against Rhabdomyolysis-Induced Acute Kidney Injury
title_sort pharmacological inhibition of fatty acid-binding protein 4 (fabp4) protects against rhabdomyolysis-induced acute kidney injury
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092613/
https://www.ncbi.nlm.nih.gov/pubmed/30135658
http://dx.doi.org/10.3389/fphar.2018.00917
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