Tubule-specific deletion of LincRNA-p21ameliorates lipotoxic kidney injury

Lipotoxicity has been implicated in the pathogenesis of obesity-related kidney damage and propagates chronic kidney injury like diabetic kidney disease; however, the underlying mechanisms have not yet been fully elucidated. To date, reduction of lipid acquisition and enhancement of lipid metabolism...

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Autores principales:	Bin Li, Joseph C.K. Leung, Loretta Y.Y. Chan, Hong-Yu Li, Wai-Han Yiu, Sarah W.Y. Lok, Rui Xue, Yi-Xin Zou, Wei Chen, Kar-Neng Lai, Sydney C.W. Tang
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	kidney obesity lipotoxicity long non-coding RNA high-fat diet palmitic acid Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/6d11bacee341458d8eb557cbe41483d8
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spelling	oai:doaj.org-article:6d11bacee341458d8eb557cbe41483d82021-11-22T04:23:46ZTubule-specific deletion of LincRNA-p21ameliorates lipotoxic kidney injury2162-253110.1016/j.omtn.2021.10.029https://doaj.org/article/6d11bacee341458d8eb557cbe41483d82021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2162253121002729https://doaj.org/toc/2162-2531Lipotoxicity has been implicated in the pathogenesis of obesity-related kidney damage and propagates chronic kidney injury like diabetic kidney disease; however, the underlying mechanisms have not yet been fully elucidated. To date, reduction of lipid acquisition and enhancement of lipid metabolism are the major, albeit non-specific, approaches to improve lipotoxic kidney damage. In the kidneys of high-fat diet (HFD)-fed mice and tubule cells cultured with palmitic acid (PA), we observed a dramatic upregulation of the long intergenic non-coding RNA-p21 (LincRNA-p21) through a p53-dependent mechanism. Kidney tubule cell-specific deletion of LincRNA-p21 attenuated oxidative stress, inflammation, apoptosis, and endoplasmic reticulum stress, leading to reduction of histological and functional kidney injury despite persistent obesity and hyperlipidemia. Mechanistically, HFD- or PA-initiated lipotoxicity suppressed the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR)/murine double minute 2 homolog (MDM2) signaling cascade to activate p53 and enhance the transcriptional activity of LincRNA-p21. Collectively, our findings suggest that the p53/LincRNA-p21 axis is the downstream effector in lipotoxic kidney injury and that targeting this axis particularly in the kidney tubule could be a novel therapeutic strategy.Bin LiJoseph C.K. LeungLoretta Y.Y. ChanHong-Yu LiWai-Han YiuSarah W.Y. LokRui XueYi-Xin ZouWei ChenKar-Neng LaiSydney C.W. TangElsevierarticlekidneyobesitylipotoxicitylong non-coding RNAhigh-fat dietpalmitic acidTherapeutics. PharmacologyRM1-950ENMolecular Therapy: Nucleic Acids, Vol 26, Iss , Pp 1280-1290 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	kidney obesity lipotoxicity long non-coding RNA high-fat diet palmitic acid Therapeutics. Pharmacology RM1-950
spellingShingle	kidney obesity lipotoxicity long non-coding RNA high-fat diet palmitic acid Therapeutics. Pharmacology RM1-950 Bin Li Joseph C.K. Leung Loretta Y.Y. Chan Hong-Yu Li Wai-Han Yiu Sarah W.Y. Lok Rui Xue Yi-Xin Zou Wei Chen Kar-Neng Lai Sydney C.W. Tang Tubule-specific deletion of LincRNA-p21ameliorates lipotoxic kidney injury
description	Lipotoxicity has been implicated in the pathogenesis of obesity-related kidney damage and propagates chronic kidney injury like diabetic kidney disease; however, the underlying mechanisms have not yet been fully elucidated. To date, reduction of lipid acquisition and enhancement of lipid metabolism are the major, albeit non-specific, approaches to improve lipotoxic kidney damage. In the kidneys of high-fat diet (HFD)-fed mice and tubule cells cultured with palmitic acid (PA), we observed a dramatic upregulation of the long intergenic non-coding RNA-p21 (LincRNA-p21) through a p53-dependent mechanism. Kidney tubule cell-specific deletion of LincRNA-p21 attenuated oxidative stress, inflammation, apoptosis, and endoplasmic reticulum stress, leading to reduction of histological and functional kidney injury despite persistent obesity and hyperlipidemia. Mechanistically, HFD- or PA-initiated lipotoxicity suppressed the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR)/murine double minute 2 homolog (MDM2) signaling cascade to activate p53 and enhance the transcriptional activity of LincRNA-p21. Collectively, our findings suggest that the p53/LincRNA-p21 axis is the downstream effector in lipotoxic kidney injury and that targeting this axis particularly in the kidney tubule could be a novel therapeutic strategy.
format	article
author	Bin Li Joseph C.K. Leung Loretta Y.Y. Chan Hong-Yu Li Wai-Han Yiu Sarah W.Y. Lok Rui Xue Yi-Xin Zou Wei Chen Kar-Neng Lai Sydney C.W. Tang
author_facet	Bin Li Joseph C.K. Leung Loretta Y.Y. Chan Hong-Yu Li Wai-Han Yiu Sarah W.Y. Lok Rui Xue Yi-Xin Zou Wei Chen Kar-Neng Lai Sydney C.W. Tang
author_sort	Bin Li
title	Tubule-specific deletion of LincRNA-p21ameliorates lipotoxic kidney injury
title_short	Tubule-specific deletion of LincRNA-p21ameliorates lipotoxic kidney injury
title_full	Tubule-specific deletion of LincRNA-p21ameliorates lipotoxic kidney injury
title_fullStr	Tubule-specific deletion of LincRNA-p21ameliorates lipotoxic kidney injury
title_full_unstemmed	Tubule-specific deletion of LincRNA-p21ameliorates lipotoxic kidney injury
title_sort	tubule-specific deletion of lincrna-p21ameliorates lipotoxic kidney injury
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/6d11bacee341458d8eb557cbe41483d8
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Tubule-specific deletion of LincRNA-p21ameliorates lipotoxic kidney injury

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