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Article: DNA methylation of FTO promotes renal inflammation by enhancing m6A of PPAR-α in alcohol-induced kidney injury

TitleDNA methylation of FTO promotes renal inflammation by enhancing m6A of PPAR-α in alcohol-induced kidney injury
Authors
KeywordsAlcoholic kidney injury
Fat mass and obesity-associated protein (FTO)
m(6)A
Peroxisome proliferator-activated receptor (PPAR)-alpha(PPAR-alpha)
Inflammation
Issue Date2021
PublisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/issn/10436618
Citation
Pharmacological Research, 2021, v. 163, p. article no. 105286 How to Cite?
AbstractAlcohol consumption is one of the risk factors for kidney injury. The underlying mechanism of alcohol-induced kidney injury remains largely unknown. We previously found that the kidney in a mouse model of alcoholic kidney injury had severe inflammation. In this study, we found that the administration of alcohol was associated with the activation of NLRP3 inflammasomes and NF-κB signaling, and the production of pro-inflammatory cytokines. Whole-genome methylation sequencing (WGBS) showed that the DNA encoding fat mass and obesity-associated protein (FTO) was significantly methylated in the alcoholic kidney. This finding was confirmed with the bisulfite sequencing (BSP), which showed that alcohol increased DNA methylation of FTO in the kidney. Furthermore, inhibition of DNA methyltransferases (DNMTs) by 5-azacytidine (5-aza) reversed alcohol-induced kidney injury and decreased the mRNA and protein levels of FTO. Importantly, we found that FTO, the m6A demethylase, epigenetically modified peroxisome proliferator activated receptor-α (PPAR-α) in a YTH domain family 2 (YTHDF2)-dependent manner, which resulted in inflammation in alcoholic kidney injury models. In conclusion, our findings indicate that alcohol increases the methylation of PPAR-α m6A by FTO-mediated YTHDF2 epigenetic modification, which ultimately leads to the activation of NLRP3 inflammasomes and NF-κB-driven renal inflammation in the kidney. These findings may provide novel strategies for preventing and treating alcoholic kidney diseases.
Persistent Identifierhttp://hdl.handle.net/10722/293644
ISSN
2023 Impact Factor: 9.1
2023 SCImago Journal Rankings: 2.160
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorYu, JT-
dc.contributor.authorHu, XW-
dc.contributor.authorChen, HY-
dc.contributor.authorYang, Q-
dc.contributor.authorLi, HD-
dc.contributor.authorDong, YH-
dc.contributor.authorZhang, Y-
dc.contributor.authorWang, JN-
dc.contributor.authorJin, J-
dc.contributor.authorWu, YG-
dc.contributor.authorLi, J-
dc.contributor.authorGe, JF-
dc.contributor.authorMeng, XM-
dc.date.accessioned2020-11-23T08:19:45Z-
dc.date.available2020-11-23T08:19:45Z-
dc.date.issued2021-
dc.identifier.citationPharmacological Research, 2021, v. 163, p. article no. 105286-
dc.identifier.issn1043-6618-
dc.identifier.urihttp://hdl.handle.net/10722/293644-
dc.description.abstractAlcohol consumption is one of the risk factors for kidney injury. The underlying mechanism of alcohol-induced kidney injury remains largely unknown. We previously found that the kidney in a mouse model of alcoholic kidney injury had severe inflammation. In this study, we found that the administration of alcohol was associated with the activation of NLRP3 inflammasomes and NF-κB signaling, and the production of pro-inflammatory cytokines. Whole-genome methylation sequencing (WGBS) showed that the DNA encoding fat mass and obesity-associated protein (FTO) was significantly methylated in the alcoholic kidney. This finding was confirmed with the bisulfite sequencing (BSP), which showed that alcohol increased DNA methylation of FTO in the kidney. Furthermore, inhibition of DNA methyltransferases (DNMTs) by 5-azacytidine (5-aza) reversed alcohol-induced kidney injury and decreased the mRNA and protein levels of FTO. Importantly, we found that FTO, the m6A demethylase, epigenetically modified peroxisome proliferator activated receptor-α (PPAR-α) in a YTH domain family 2 (YTHDF2)-dependent manner, which resulted in inflammation in alcoholic kidney injury models. In conclusion, our findings indicate that alcohol increases the methylation of PPAR-α m6A by FTO-mediated YTHDF2 epigenetic modification, which ultimately leads to the activation of NLRP3 inflammasomes and NF-κB-driven renal inflammation in the kidney. These findings may provide novel strategies for preventing and treating alcoholic kidney diseases.-
dc.languageeng-
dc.publisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/issn/10436618-
dc.relation.ispartofPharmacological Research-
dc.subjectAlcoholic kidney injury-
dc.subjectFat mass and obesity-associated protein (FTO)-
dc.subjectm(6)A-
dc.subjectPeroxisome proliferator-activated receptor (PPAR)-alpha(PPAR-alpha)-
dc.subjectInflammation-
dc.titleDNA methylation of FTO promotes renal inflammation by enhancing m6A of PPAR-α in alcohol-induced kidney injury-
dc.typeArticle-
dc.identifier.emailChen, HY: haiyong@hku.hk-
dc.identifier.authorityChen, HY=rp01923-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.phrs.2020.105286-
dc.identifier.pmid33157234-
dc.identifier.scopuseid_2-s2.0-85095824288-
dc.identifier.hkuros319872-
dc.identifier.volume163-
dc.identifier.spagearticle no. 105286-
dc.identifier.epagearticle no. 105286-
dc.identifier.isiWOS:000609226800046-
dc.publisher.placeUnited Kingdom-

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