Rhein Improves Renal Fibrosis by Restoring Cpt1a-Mediated Fatty Acid Oxidation through SirT1/STAT3/twist1 Pathway

The latest progress in the field of renal fibrosis mainly focuses on the new concept of "partial epithelial-mesenchymal transition (pEMT)" to explain the contribution of renal tubular epithelial (RTE) cells to renal fibrosis and the crucial role of fatty acid oxidation (FAO) dysfunction in...

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Bibliographic Details
Published in:	Molecules (Basel, Switzerland) Vol. 27; no. 7; p. 2344
Main Authors:	Song, Xianrui, Du, Zesen, Yao, Zhenqi, Tang, Xiaoyan, Zhang, Mian
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 06-04-2022 MDPI
Subjects:	Animals Anthraquinones - pharmacology Atrophy Carnitine O-Palmitoyltransferase - metabolism Collagen Cpt1a-mediated fatty acid oxidation Depletion Enzymes Epithelial-Mesenchymal Transition Extracellular matrix Fatty acids Fatty Acids - metabolism Fibrosis Genes Genomes Inflammation Kidney Diseases - drug therapy Kidney Diseases - pathology Kidneys Lipids Mesenchyme Metabolism Metabolites Metabolomics Oxidation Rats renal fibrosis rhein SIRT1 protein SirT1/STAT3 pathway Sirtuin 1 Stat3 protein STAT3 Transcription Factor Substrate inhibition Transcription factors Transcriptomics Twist-Related Protein 1 Twist1 epithelial–mesenchymal transition rhein Cpt1a-mediated fatty acid oxidation SirT1/STAT3 pathway renal fibrosis Twist1
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Summary:	The latest progress in the field of renal fibrosis mainly focuses on the new concept of "partial epithelial-mesenchymal transition (pEMT)" to explain the contribution of renal tubular epithelial (RTE) cells to renal fibrosis and the crucial role of fatty acid oxidation (FAO) dysfunction in RTE cells for the development of renal fibrosis. FAO depression is considered to be secondary or occur simultaneously with pEMT. We explored the relationship between pEMT and FAO and the effect of rhein on them. Intragastric administration of rhein significantly improved the levels of BUN, Scr, α-SMA, collagen 1A and histopathological changes in UUO-rats. Transcriptomic and metabolomic analyses revealed that abnormal signaling pathways were involved in EMT and FAO disorders. RTE cell experiments showed that TGF-β could inhibit the activity of Cpt1a, resulting in ATP depletion and lipid deposition. Cpt1a inhibitor induced EMT, while Cpt1 substrate or rhein inhibited EMT, indicating that Cpt1a-mediated FAO dysfunction is essential for RTE cells EMT. Further studies showed that Cpt1a activity were regulated by SirT1/STAT3/Twist1 pathway. Rhein inhibits RTE cell EMT by promoting Cpt1a-mediated FAO through the SirT1/STAT3/Twist1 pathway. Surprisingly and importantly, our experiments showed that FAO depression occurs before EMT, and EMT is one of the results of FAO depression.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1420-3049 1420-3049
DOI:	10.3390/molecules27072344