TP53RK Drives the Progression of Chronic Kidney Disease by Phosphorylating Birc5

Wu, Mengqiu; Jin, Qianqian; Xu, Xinyue; Fan, Jinhui; Chen, Weiyi; Miao, Mengqiu; Gu, Ran; Zhang, Shengnan; Guo, Yan; Huang, Songming; Zhang, Yue; Zhang, Aihua

doi:10.1002/advs.202301753

Cited by 3 publications

References 49 publications

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The Spermine Oxidase/Spermine Axis Coordinates ATG5‐Mediated Autophagy to Orchestrate Renal Senescence and Fibrosis

Luo,

Lu,

et al. 2024

Advanced Science

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Decreased plasma spermine levels are associated with kidney dysfunction. However, the role of spermine in kidney disease remains largely unknown. Herein, it is demonstrated that spermine oxidase (SMOX), a key enzyme governing polyamine metabolism, is predominantly induced in tubular epithelium of human and mouse fibrotic kidneys, alongside a reduction in renal spermine content in mice. Moreover, renal SMOX expression is positively correlated with kidney fibrosis and function decline in patients with chronic kidney disease. Importantly, supplementation with exogenous spermine or genetically deficient SMOX markedly improves autophagy, reduces senescence, and attenuates fibrosis in mouse kidneys. Further, downregulation of ATG5, a critical component of autophagy, in tubular epithelial cells enhances SMOX expression and reduces spermine in TGF‐β1‐induced fibrogenesis in vitro and kidney fibrosis in vivo. Mechanically, ATG5 readily interacts with SMOX under physiological conditions and in TGF‐β1‐induced fibrogenic responses to preserve cellular spermine levels. Collectively, the findings suggest SMOX/spermine axis is a potential novel therapy to antagonize renal fibrosis, possibly by coordinating autophagy and suppressing senescence.

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The Spermine Oxidase/Spermine Axis Coordinates ATG5‐Mediated Autophagy to Orchestrate Renal Senescence and Fibrosis

Luo,

Lu,

et al. 2024

Advanced Science

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DY131 activates ERRγ/TFAM axis to protect against metabolic disorders and acute kidney injury

Gong,

Lu,

et al. 2024

Clinical Science

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Renal tubular injury is considered as the main pathological feature of acute kidney injury (AKI), and mitochondrial dysfunction in renal tubular cells is implicated in the pathogenesis of AKI. The estrogen-related receptor γ (ERRγ) is a member of orphan nuclear receptors which plays a regulatory role in mitochondrial biosynthesis, energy metabolism and many metabolic pathways. Online datasets showed a dominant expression of ERRγ in renal tubules, but the role of ERRγ in AKI is still unknown. In the present study, we investigated the role of ERRγ in the pathogenesis of AKI and the therapeutic efficacy of ERRγ agonist DY131 in several murine models of AKI. ERRγ expression was reduced in kidneys of AKI patients and AKI murine models along with a negative correlation to the severity of AKI. Consistently, silencing ERRγ in vitro enhanced cisplatin-induced tubular cells apoptosis, while ERRγ overexpression in vivo utilizing hydrodynamic-based tail vein plasmid delivery approach alleviated cisplatin-induced AKI. ERRγ agonist DY131 could enhance the transcriptional activity of ERRγ and ameliorate AKI in various murine models. Moreover, DY131 attenuated the mitochondrial dysfunction of renal tubular cells and metabolic disorders of kidneys in AKI, and promoted the expression of the mitochondrial transcriptional factor A (TFAM). Further investigation showed that TFAM could be a target gene of ERRγ and DY131 might ameliorate AKI by enhancing ERRγ-mediated TFAM expression protecting mitochondria. These findings highlighted the protective effect of DY131 on AKI, thus providing a promising therapeutic strategy for AKI.

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Bioinformatics and next generation data analysis reveals the potential role of inflammation in sepsis and its associated complications

Vastrad¹,

Vastrad²

2023

Preprint

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Sepsis is the leading systemic inflammatory response syndrome in worldwide, yet relatively little is known about the genes and signaling pathways involved in sepsis progression. The current investigation aimed to elucidate potential key candidate genes and pathways in sepsis and its associated complications. Next generation sequencing (NGS) dataset (GSE185263) was downloaded from the Gene Expression Omnibus (GEO) database, which included data from 348 sepsis samples and 44 normal control samples. Differentially expressed genes (DEGs) were identified using t-tests in the DESeq2 R package. Next, we made use of the g:Profiler to analyze gene ontology (GO) and REACTOME pathway. Then protein-protein interaction (PPI) of these DEGs was visualized by Cytoscape with Search Tool for the Retrieval of Interacting Genes (STRING). Furthermore, we constructed miRNA-hub gene regulatory network and TF-hub gene regulatory network among hub genes utilizing miRNet and NetworkAnalyst online databases tool and Cytoscape software. Finally, we performed receiver operating characteristic (ROC) curve analysis of hub genes through the pROC package in R statistical software. In total, 958 DEGs were identified, of which 479 were up regulated and 479 were down regulated. GO and REACTOME results showed that DEGs mainly enriched in regulation of cellular process, response to stimulus, extracellular matrix organization and immune system. The hub genes of PRKN, KIT, FGFR2, GATA3, ERBB3, CDK1, PPARG, H2BC5, H4C4 and CDC20 might be associated with sepsis and its associated complications. Predicted miRNAs (e.g., hsa-mir-548ad-5p and hsa-mir-2113) and TFs (e.g., YAP1 and TBX5) were found to be significantly correlated with sepsis and its associated complications. In conclusion, the DEGs, relative pathways, hub genes, miRNA and TFs identified in the current investigation might help in understanding of the molecular mechanisms underlying sepsis and its associated complications progression and provide potential molecular targets and biomarkers for sepsis and its associated complications.

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TP53RK Drives the Progression of Chronic Kidney Disease by Phosphorylating Birc5

Cited by 3 publications

References 49 publications

The Spermine Oxidase/Spermine Axis Coordinates ATG5‐Mediated Autophagy to Orchestrate Renal Senescence and Fibrosis

The Spermine Oxidase/Spermine Axis Coordinates ATG5‐Mediated Autophagy to Orchestrate Renal Senescence and Fibrosis

DY131 activates ERRγ/TFAM axis to protect against metabolic disorders and acute kidney injury

Bioinformatics and next generation data analysis reveals the potential role of inflammation in sepsis and its associated complications

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