Tackling AKI: prevention, timing of dialysis and follow-up

Vijayan, Anitha

doi:10.1038/s41581-020-00390-3

Cited by 64 publications

(38 citation statements)

References 9 publications

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“…Acute kidney injury (AKI) is a common and severe condition in which renal function declines rapidly in a short time 1 . AKI is associated with high morbidity and mortality in hospitalized patients 2 - 5 .…”

Section: Introductionmentioning

confidence: 99%

DUSP2-mediated inhibition of tubular epithelial cell pyroptosis confers nephroprotection in acute kidney injury

Xiong¹,

Ran²,

Yingguo³

et al. 2022

Theranostics

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Rationale: Acute kidney injury (AKI) is pathologically characterized by renal tubular epithelial cell (RTEC) death and interstitial inflammation, while their pathogenesis remains incompletely understood. Dual-specificity phosphatase 2 (DUSP2) recently emerges as a crucial regulator of cell death and inflammation in a wide range of diseases, but its roles in renal pathophysiology are largely unknown. Methods: The expression of DUSP2 in the kidney was characterized by histological analysis in renal tissues from patients and mice with AKI. The role and mechanism of DUSP2-mediated inhibition of tubular epithelial cell pyroptosis in AKI were evaluated both in vivo and in vitro , and confirmed in RTEC-specific deletion of DUSP2 mice. Results: Here, we show that DUSP2 is enriched in RTECs in the renal tissue of both human and mouse and mainly positions in the nucleus. Further, we reveal that loss-of-DUSP2 in RTECs not only is a common feature of human and murine AKI but also positively contributes to AKI pathogenesis. Especially, RTEC-specific deletion of DUSP2 sensitizes mice to AKI by promoting RTEC pyroptosis and the resultant interstitial inflammation. Mechanistic studies show that gasdermin D (GSDMD), which mediates RTEC pyroptosis, is identified as a transcriptional target of activated STAT1 during AKI, whereas DUSP2 as a nuclear phosphatase deactivates STAT1 to restrict GSDMD-mediated RTEC pyroptosis. Importantly, DUSP2 overexpression in RTECs via adeno-associated virus-mediated gene transfer significantly ameliorates AKI. Conclusion: Our findings demonstrate a hitherto unrecognized role of DUSP2-STAT1 axis in regulating RTEC pyroptosis in AKI, highlighting that DUSP2-STAT1 axis is an attractive therapeutic target for AKI.

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Section: Introductionmentioning

confidence: 99%

DUSP2-mediated inhibition of tubular epithelial cell pyroptosis confers nephroprotection in acute kidney injury

Xiong¹,

Ran²,

Yingguo³

et al. 2022

Theranostics

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“…The incidence of sepsis-induced acute kidney injury (S-AKI) in the intensive care unit is extremely high, and it is one of the risk factors for death in patients with sepsis [ 4 ]. S-AKI has high morbidity and mortality especially in young children and old adults, coming with heavy burdens both on the health and economy [ 5 , 6 ]. As defined by KDIGO (kidney disease: improving global outcomes), S-AKI is characterized by an increase in serum creatinine (Cr) within 48 hours and extremely low urine output and manifested as a clinical syndrome of water electrolyte and acid base balance disorders and azotemia [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

miR-181a-5p Inhibits Pyroptosis in Sepsis-Induced Acute Kidney Injury through Downregulation of NEK7

Zhang

Zhi

Lin

et al. 2022

Journal of Immunology Research

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Sepsis is a life-threatening organ dysfunction caused by the uncontrolled inflammation, easily affecting the kidney. Sepsis-induced acute kidney injury (S-AKI) has high morbidity and mortality, of which the pathophysiological mechanisms have not been completely illuminated, leading to nonspecific therapies. Specific microRNAs were related with the pathogenesis of AKI. However, only limited studies focused on the pyroptosis in the context of S-AKI. The in vitro LPS-induced HK-2 cell model and in vivo CLP-induced mouse model were established. qRT-PCR, Western blot, ELISA, and RNA pulldown were used for expression examination. Multiple biological databases were used for miRNA screening. H&E staining and IHC staining were performed. The LPS-induced HK-2 cells showed significantly increased ( P < 0.01 ) fluorescence intensity of N-GSDMD and ASC compared with the HK-2 cells. The expression of NLRP3, NEK7, ASC, active caspase-1, and N-GSDMD was significantly enhanced ( P < 0.05 ) and the inflammatory factors including IL-18, IL-1β, and THF-α were all increased in LPS-induced HK-2 cells and CLP-induced mice. Renal edema, serum Cr and BUN, and expression of KIM-1 and NGAL were significantly higher ( P < 0.05 ) in CLP-induced S-AKI mice than the sham group. miR-101-3p, miR-144-3p, miR-181a-5p, miR-4262, and miR-513b-5p could inhibit NEK7. NEK7 is an interacting protein of miRNA-181a-5p. miR-181a-5p inhibits pyroptosis of the LPS-induced HK-2 cells through downregulation of NEK7. Pyroptosis of HK-2 cells promotes inflammation. miR-181a-5p inhibits pyroptosis through downregulation of NEK7 in LPS-induced HK-2 cells and CLP-induced mice. Our study indicated miR-181a-5p as a new potential therapeutic target for S-AKI therapy.

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“…The current diagnosis of AKI still relies on serum creatinine and urine output. 5 Unfortunately, owing to the lag time between the onset of injury and changes in serum creatinine and urine output, the diagnosis is often not clarified until after the initiation and extension phases of kidney injury have transitioned to the maintenance phase of injury. 6 The available evidence suggests that even mild AKI is associated with increased mortality.…”

Section: Introductionmentioning

confidence: 99%

Identifying of miRNA–mRNA Regulatory Networks Associated with Acute Kidney Injury by Weighted Gene Co-Expression Network Analysis

Xu¹,

Xu²

2022

IJGM

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Background Acute kidney injury (AKI) is a clinical emergency characterized by a dramatic decline in renal function and the accumulation of metabolic waste products in the body, with a high morbidity and mortality rate. The pathogenesis of AKI remains unclear and there are no effective treatment options. Methods We aimed to identify critical genes involved in the pathogenesis of AKI and construct a miRNA–mRNA regulatory network using gene expression data downloaded from Gene Expression Omnibus (GSE85957) for 38 kidneys of AKI and 19 control rats and cisplatin treated kidneys of 3 AKI and 3 control rats. Data in GSE85957 were processed using weighted gene co-expression network analysis (WGCNA), and biological function analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used to analyze the functions associated with critical genes. Results Twenty-eight modules in the GSE85957 dataset were identified by WGCNA, of which 103 genes in the orange module and 30 genes in the black module were closely associated with AKI and dose. Biological function analysis of genes in the orange and black modules revealed that skeletal muscle cell differentiation, tissue development and organ development were involved in the pathological changes of AKI. Combining with our experimentally processed AKI rat kidney data, eight genes (Atf3, Egr1, Egr2, Fos, Fosb, Gdf15, Serpine1 and Nr1d1) were identified as potential biomarkers of AKI, and miRNA–mRNA regulatory networks were constructed based on the above eight critical genes. Further tissue validation revealed that Egr1 and Fos were highly expressed in AKI. Conclusion Our study identified potential biomarkers of AKI and constructed an associated miRNA–mRNA regulatory network, which may provide new insights into the molecular pathogenesis of AKI.

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Tackling AKI: prevention, timing of dialysis and follow-up

Cited by 64 publications

References 9 publications

DUSP2-mediated inhibition of tubular epithelial cell pyroptosis confers nephroprotection in acute kidney injury

DUSP2-mediated inhibition of tubular epithelial cell pyroptosis confers nephroprotection in acute kidney injury

miR-181a-5p Inhibits Pyroptosis in Sepsis-Induced Acute Kidney Injury through Downregulation of NEK7

Identifying of miRNA–mRNA Regulatory Networks Associated with Acute Kidney Injury by Weighted Gene Co-Expression Network Analysis

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