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Tubule-specific deletion of LincRNA-p21ameliorates lipotoxic kidney injury.

ABSTRACT: 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.

SUBMITTER: Li B

PROVIDER: S-EPMC8609107 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Tubule-specific deletion of <i>LincRNA-p21</i>ameliorates lipotoxic kidney injury.

Li Bin B Leung Joseph C K JCK Chan Loretta Y Y LYY Li Hong-Yu HY Yiu Wai-Han WH Lok Sarah W Y SWY Xue Rui R Zou Yi-Xin YX Chen Wei W Lai Kar-Neng KN Tang Sydney C W SCW

Molecular therapy. Nucleic acids 20211104

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 drama ...[more]

PMID: 34853727

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Project description:BackgroundAcute kidney injury (AKI) is associated with a severe decline in kidney function caused by abnormalities within the podocytes' glomerular matrix. Recently, AKI has been linked to alterations in glycolysis and the activity of glycolytic enzymes, including pyruvate kinase M2 (PKM2). However, the contribution of this enzyme to AKI remains largely unexplored.MethodsCre-loxP technology was used to examine the effects of PKM2 specific deletion in podocytes on the activation status of key signaling pathways involved in the pathophysiology of AKI by lipopolysaccharides (LPS). In addition, we used lentiviral shRNA to generate murine podocytes deficient in PKM2 and investigated the molecular mechanisms mediating PKM2 actions in vitro.ResultsSpecific PKM2 deletion in podocytes ameliorated LPS-induced protein excretion and alleviated LPS-induced alterations in blood urea nitrogen and serum albumin levels. In addition, PKM2 deletion in podocytes alleviated LPS-induced structural and morphological alterations to the tubules and to the brush borders. At the molecular level, PKM2 deficiency in podocytes suppressed LPS-induced inflammation and apoptosis. In vitro, PKM2 knockdown in murine podocytes diminished LPS-induced apoptosis. These effects were concomitant with a reduction in LPS-induced activation of β-catenin and the loss of Wilms' Tumor 1 (WT1) and nephrin. Notably, the overexpression of a constitutively active mutant of β-catenin abolished the protective effect of PKM2 knockdown. Conversely, PKM2 knockdown cells reconstituted with the phosphotyrosine binding-deficient PKM2 mutant (K433E) recapitulated the effect of PKM2 depletion on LPS-induced apoptosis, β-catenin activation, and reduction in WT1 expression.ConclusionsTaken together, our data demonstrates that PKM2 plays a key role in podocyte injury and suggests that targetting PKM2 in podocytes could serve as a promising therapeutic strategy for AKI.Trial registrationNot applicable. Video abstract.

Dataset Information

Tubule-specific deletion of LincRNA-p21ameliorates lipotoxic kidney injury.

Publications

Tubule-specific deletion of <i>LincRNA-p21</i>ameliorates lipotoxic kidney injury.

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