Tubule-specific deletion of LincRNA-p21ameliorates lipotoxic kidney injury
| Autor: | Yi-Xin Zou, Sydney C.W. Tang, Loretta Y.Y. Chan, Joseph Leung, Hongyu Li, Rui Xue, Kar-Neng Lai, Wai-Han Yiu, Bin Li, Sarah W.Y. Lok, Wei Chen |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
p53
kidney obesity tubule cell RM1-950 Downregulation and upregulation Drug Discovery medicine palmitic acid Protein kinase B Mechanistic target of rapamycin PI3K/AKT/mTOR pathway Kidney biology long non-coding RNA Chemistry Lipid metabolism lipotoxicity Cell biology Tubule medicine.anatomical_structure high-fat diet Lipotoxicity inflammation biology.protein Molecular Medicine Original Article Therapeutics. Pharmacology |
| Zdroj: | Molecular Therapy. Nucleic Acids Molecular Therapy: Nucleic Acids, Vol 26, Iss, Pp 1280-1290 (2021) |
| ISSN: | 2162-2531 |
| Popis: | 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. Graphical abstract Our study observed a dramatic upregulation of LincRNA-p21 through a p53-dependent mechanism in kidney tubule cells exposed to palmitic acid. Tubule cell-specific deletion of LincRNA-p21 prevented histological and functional kidney injury induced by high-fat diet. These findings suggest p53/LincRNA-p21 signaling axis as a potential therapeutic target for lipotoxic kidney injury. |
| Databáze: | OpenAIRE |
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