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Article: Smad3 promotes AKI sensitivity in diabetic mice via interaction with p53 and induction of NOX4-dependent ROS production

TitleSmad3 promotes AKI sensitivity in diabetic mice via interaction with p53 and induction of NOX4-dependent ROS production
Authors
KeywordsSmad
TGF-β
Diabetic nephropathy
AKI
Inflammation
Issue Date2020
PublisherElsevier: Creative Commons. The Journal's web site is located at http://www.journals.elsevier.com/redox-biology
Citation
Redox Biology, 2020, v. 32, p. article no. 101479 How to Cite?
AbstractThe incidence and severity of acute kidney injury (AKI) is increased yearly in diabetic patients. Although the mechanisms for this remain unclear, the prevention of AKI in diabetic nephropathy is feasible and of value. As we detected highly activation of TGF-β/Smad3 signaling in both human biopsy and mouse model of diabetic nephropathy, we hypothesized that Smad3 activation in diabetic kidneys may increase AKI sensitivity. We tested our hypothesis in vitro using TGF-β type II receptor (TGF-βRII) disrupted tubular epithelial cells (TECs) and in vivo in mice with streptozotocin (STZ)-induced diabetic nephropathy before the induction of ischemia/reperfusion (I/R) injury. We found that high glucose (HG)-cultured TECs showed increased inflammation, apoptosis and oxidative stress following hypoxia/reoxygenation (H/R) injury. Disruption of TGF-βRII attenuated cell injury induced by H/R in HG-treated TECs. Consistently, Smad3 knockdown in diabetic kidney attenuated I/R-induced AKI. Mechanistically, Smad3 binds to p53 and enhances p53 activity in cells treated with HG and H/R, which may lead to TECs apoptosis. Additionally, ChIP assay showed that Smad3 bound with the promoter region of NOX4 and induced ROS production and inflammation. In conclusion, our results demonstrate that Smad3 promotes AKI susceptibility in diabetic mice by interacting with p53 and NOX4.
Persistent Identifierhttp://hdl.handle.net/10722/287328
ISSN
2019 Impact Factor: 9.986
2015 SCImago Journal Rankings: 2.382
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorWang, JN-
dc.contributor.authorYang, Q-
dc.contributor.authorYang, C-
dc.contributor.authorCai, YT-
dc.contributor.authorXing, T-
dc.contributor.authorGao, L-
dc.contributor.authorWang, F-
dc.contributor.authorChen, X-
dc.contributor.authorLiu, XQ-
dc.contributor.authorHe, XY-
dc.contributor.authorWei, B-
dc.contributor.authorJiang, L-
dc.contributor.authorLi, C-
dc.contributor.authorJin, J-
dc.contributor.authorWen, JG-
dc.contributor.authorMa, TT-
dc.contributor.authorChen, HY-
dc.contributor.authorLi, J-
dc.contributor.authorMeng, XM-
dc.date.accessioned2020-09-22T02:59:22Z-
dc.date.available2020-09-22T02:59:22Z-
dc.date.issued2020-
dc.identifier.citationRedox Biology, 2020, v. 32, p. article no. 101479-
dc.identifier.issn2213-2317-
dc.identifier.urihttp://hdl.handle.net/10722/287328-
dc.description.abstractThe incidence and severity of acute kidney injury (AKI) is increased yearly in diabetic patients. Although the mechanisms for this remain unclear, the prevention of AKI in diabetic nephropathy is feasible and of value. As we detected highly activation of TGF-β/Smad3 signaling in both human biopsy and mouse model of diabetic nephropathy, we hypothesized that Smad3 activation in diabetic kidneys may increase AKI sensitivity. We tested our hypothesis in vitro using TGF-β type II receptor (TGF-βRII) disrupted tubular epithelial cells (TECs) and in vivo in mice with streptozotocin (STZ)-induced diabetic nephropathy before the induction of ischemia/reperfusion (I/R) injury. We found that high glucose (HG)-cultured TECs showed increased inflammation, apoptosis and oxidative stress following hypoxia/reoxygenation (H/R) injury. Disruption of TGF-βRII attenuated cell injury induced by H/R in HG-treated TECs. Consistently, Smad3 knockdown in diabetic kidney attenuated I/R-induced AKI. Mechanistically, Smad3 binds to p53 and enhances p53 activity in cells treated with HG and H/R, which may lead to TECs apoptosis. Additionally, ChIP assay showed that Smad3 bound with the promoter region of NOX4 and induced ROS production and inflammation. In conclusion, our results demonstrate that Smad3 promotes AKI susceptibility in diabetic mice by interacting with p53 and NOX4.-
dc.languageeng-
dc.publisherElsevier: Creative Commons. The Journal's web site is located at http://www.journals.elsevier.com/redox-biology-
dc.relation.ispartofRedox Biology-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectSmad-
dc.subjectTGF-β-
dc.subjectDiabetic nephropathy-
dc.subjectAKI-
dc.subjectInflammation-
dc.titleSmad3 promotes AKI sensitivity in diabetic mice via interaction with p53 and induction of NOX4-dependent ROS production-
dc.typeArticle-
dc.identifier.emailChen, HY: haiyong@hku.hk-
dc.identifier.authorityChen, HY=rp01923-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1016/j.redox.2020.101479-
dc.identifier.pmid32143149-
dc.identifier.pmcidPMC7058410-
dc.identifier.scopuseid_2-s2.0-85080111051-
dc.identifier.hkuros314529-
dc.identifier.volume32-
dc.identifier.spagearticle no. 101479-
dc.identifier.epagearticle no. 101479-
dc.publisher.placeNetherlands-

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