Amelioration of renal inflammation, endoplasmic reticulum stress and apoptosis underlies the protective effect of low dosage of atorvastatin in gentamicin-induced nephrotoxicity

© 2016 Jaikumkao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Gentamicin is a commonly used aminoglyco...

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Main Authors: Krit Jaikumkao, Anchalee Pongchaidecha, La Ongdao Thongnak, Keerati Wanchai, Phatchawan Arjinajarn, Varanuj Chatsudthipong, Nipon Chattipakorn, Anusorn Lungkaphin
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Published: 2018
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spelling th-cmuir.6653943832-549652018-09-05T02:52:19Z Amelioration of renal inflammation, endoplasmic reticulum stress and apoptosis underlies the protective effect of low dosage of atorvastatin in gentamicin-induced nephrotoxicity Krit Jaikumkao Anchalee Pongchaidecha La Ongdao Thongnak Keerati Wanchai Phatchawan Arjinajarn Varanuj Chatsudthipong Nipon Chattipakorn Anusorn Lungkaphin Agricultural and Biological Sciences Biochemistry, Genetics and Molecular Biology © 2016 Jaikumkao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Gentamicin is a commonly used aminoglycoside antibiotic. However, its therapeutic use is limited by its nephrotoxicity. The mechanisms of gentamicin-induced nephrotoxicity are principally from renal inflammation and oxidative stress. Since atorvastatin, 3-hydroxy-3- methylglutaryl coenzyme A reductase inhibitors, exerts lipid-lowering effects, antioxidant, anti-inflammatory as well as anti-apoptotic effects, this study aimed to investigate the protective effects of atorvastatin against gentamicin-induced nephrotoxicity. Male Sprague Dawley rats were used and nephrotoxicity was induced by intraperitoneal injection of gentamicin, 100 mg/kg/day, for 15 days. Atorvastatin, 10 mg/kg/day, was administered by orally gavage 30 min before gentamicin injection on day 1 to 15 (pretreatment) or on day 10 to15 (delayed treatment). For only atorvastatin treatment group, it was given on day 1 to 15. At the end of the experiment, kidney weight, blood urea nitrogen and serum creatinine as well as renal inflammation (NF-κB, TNFαR1, IL-6 and iNOS), renal fibrosis (TGFβ1), ER stress (calpain, GRP78, CHOP, and caspase 12) and apoptotic markers (cleaved caspase-3, Bax, and Bcl-2) as well as TUNEL assay were determined. Gentamicin-induced nephrotoxicity was confirmed by marked elevations in serum urea and creatinine, kidney hypertrophy, renal inflammation, fibrosis, ER stress and apoptosis and attenuation of creatinine clearance. Atorvastatin pre and delayed treatment significantly improved renal function and decreased renal NF-κB, TNFαR1, IL-6, iNOS and TGFβ1 expressions. They also attenuated calpain, GRP78, CHOP, caspase 12, Bax, and increased Bcl-2 expressions in gentamicin- treated rat. These results indicate that atorvastatin treatment could attenuate gentamicin-induced nephrotoxicity in rats, substantiated by the reduction of inflammation, ER stress and apoptosis. The effect of atorvastatin in protecting from renal damage induced by gentamicin seems to be more effective when it beginning given along with gentamicin or pretreatment. 2018-09-05T02:50:28Z 2018-09-05T02:50:28Z 2016-10-01 Journal 19326203 2-s2.0-84991451286 10.1371/journal.pone.0164528 https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84991451286&origin=inward http://cmuir.cmu.ac.th/jspui/handle/6653943832/54965
institution Chiang Mai University
building Chiang Mai University Library
country Thailand
collection CMU Intellectual Repository
topic Agricultural and Biological Sciences
Biochemistry, Genetics and Molecular Biology
spellingShingle Agricultural and Biological Sciences
Biochemistry, Genetics and Molecular Biology
Krit Jaikumkao
Anchalee Pongchaidecha
La Ongdao Thongnak
Keerati Wanchai
Phatchawan Arjinajarn
Varanuj Chatsudthipong
Nipon Chattipakorn
Anusorn Lungkaphin
Amelioration of renal inflammation, endoplasmic reticulum stress and apoptosis underlies the protective effect of low dosage of atorvastatin in gentamicin-induced nephrotoxicity
description © 2016 Jaikumkao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Gentamicin is a commonly used aminoglycoside antibiotic. However, its therapeutic use is limited by its nephrotoxicity. The mechanisms of gentamicin-induced nephrotoxicity are principally from renal inflammation and oxidative stress. Since atorvastatin, 3-hydroxy-3- methylglutaryl coenzyme A reductase inhibitors, exerts lipid-lowering effects, antioxidant, anti-inflammatory as well as anti-apoptotic effects, this study aimed to investigate the protective effects of atorvastatin against gentamicin-induced nephrotoxicity. Male Sprague Dawley rats were used and nephrotoxicity was induced by intraperitoneal injection of gentamicin, 100 mg/kg/day, for 15 days. Atorvastatin, 10 mg/kg/day, was administered by orally gavage 30 min before gentamicin injection on day 1 to 15 (pretreatment) or on day 10 to15 (delayed treatment). For only atorvastatin treatment group, it was given on day 1 to 15. At the end of the experiment, kidney weight, blood urea nitrogen and serum creatinine as well as renal inflammation (NF-κB, TNFαR1, IL-6 and iNOS), renal fibrosis (TGFβ1), ER stress (calpain, GRP78, CHOP, and caspase 12) and apoptotic markers (cleaved caspase-3, Bax, and Bcl-2) as well as TUNEL assay were determined. Gentamicin-induced nephrotoxicity was confirmed by marked elevations in serum urea and creatinine, kidney hypertrophy, renal inflammation, fibrosis, ER stress and apoptosis and attenuation of creatinine clearance. Atorvastatin pre and delayed treatment significantly improved renal function and decreased renal NF-κB, TNFαR1, IL-6, iNOS and TGFβ1 expressions. They also attenuated calpain, GRP78, CHOP, caspase 12, Bax, and increased Bcl-2 expressions in gentamicin- treated rat. These results indicate that atorvastatin treatment could attenuate gentamicin-induced nephrotoxicity in rats, substantiated by the reduction of inflammation, ER stress and apoptosis. The effect of atorvastatin in protecting from renal damage induced by gentamicin seems to be more effective when it beginning given along with gentamicin or pretreatment.
format Journal
author Krit Jaikumkao
Anchalee Pongchaidecha
La Ongdao Thongnak
Keerati Wanchai
Phatchawan Arjinajarn
Varanuj Chatsudthipong
Nipon Chattipakorn
Anusorn Lungkaphin
author_facet Krit Jaikumkao
Anchalee Pongchaidecha
La Ongdao Thongnak
Keerati Wanchai
Phatchawan Arjinajarn
Varanuj Chatsudthipong
Nipon Chattipakorn
Anusorn Lungkaphin
author_sort Krit Jaikumkao
title Amelioration of renal inflammation, endoplasmic reticulum stress and apoptosis underlies the protective effect of low dosage of atorvastatin in gentamicin-induced nephrotoxicity
title_short Amelioration of renal inflammation, endoplasmic reticulum stress and apoptosis underlies the protective effect of low dosage of atorvastatin in gentamicin-induced nephrotoxicity
title_full Amelioration of renal inflammation, endoplasmic reticulum stress and apoptosis underlies the protective effect of low dosage of atorvastatin in gentamicin-induced nephrotoxicity
title_fullStr Amelioration of renal inflammation, endoplasmic reticulum stress and apoptosis underlies the protective effect of low dosage of atorvastatin in gentamicin-induced nephrotoxicity
title_full_unstemmed Amelioration of renal inflammation, endoplasmic reticulum stress and apoptosis underlies the protective effect of low dosage of atorvastatin in gentamicin-induced nephrotoxicity
title_sort amelioration of renal inflammation, endoplasmic reticulum stress and apoptosis underlies the protective effect of low dosage of atorvastatin in gentamicin-induced nephrotoxicity
publishDate 2018
url https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84991451286&origin=inward
http://cmuir.cmu.ac.th/jspui/handle/6653943832/54965
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