Role of promoting inflammation of Krüppel-like factor 6 in acute kidney injury

Li, Dan; Liu, Xiaoqiang; Li, Chenyu; Zhang, Yue; Chen, Guan; Huang, Junyan; Xu, Yan

doi:10.1080/0886022x.2020.1793353

Cited by 12 publications

(10 citation statements)

References 48 publications

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“…KLF6 belongs to the zinc finger family and regulates the expressions of genes associated with signal transduction, cell cycle, and inflammation [37]. KLF6 participates in the mechanisms of AKI by elevating the levels of inflammatory cytokines [38]. Our results verified that circHIPK3 could upregulate the KLF6 level by competitively binding to miR-124-3p.…”

Section: Discussionsupporting

confidence: 70%

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Mechanism of circHIPK3-miRNA-124-3p/miRNA-148b-3p-Mediated Inflammatory Responses and Cell Senescence in Candida albicans-Induced Septic Acute Kidney Injury

Han

Zhang

et al. 2022

Gerontology

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Introduction: Sepsis is a life-threatening inflammatory state that can result in septic acute kidney injury (SAKI). Circular RNAs (circRNAs) are implicated in various inflammatory diseases including SAKI. This study investigated the effect of circHIPK3 on inflammatory responses and cell senescence in Candida albicans-induced SAKI. Methods: circHIPK3 expression and inflammatory factors in the serum of SAKI patients and healthy volunteers were detected. The murine and cell models of SAKI were established by C. albicans and lipopolysaccharide induction, respectively. The effect of circHIPK3 on SAKI inflammatory responses and cell senescence was measured using ELISA, SA-β-gal staining, CCK-8, RT-qPCR, and Western blot. The binding relationships among circHIPK3, miR-124-3p, or miR-148b-3p and KLF6 or DNMT1/3a were confirmed. The binding of KLF6 and NLRP3 was determined, and the methylation level of the Klotho promoter was detected. Functional rescue experiments were performed to verify the effect of miR-124-3p or miR-148b-3p on SAKI. Results: circHIPK3 was highly expressed in SAKI. circHIPK3 silencing alleviated kidney injury in SAKI mice and enhanced SAKI cell viability by alleviating inflammatory responses and cell senescence. Mechanically, circHIPK3 upregulated KLF6 expression by competitively binding to miR-124-3p, thereby promoting the binding of KLF6 and NLRP3, activating NLRP3/caspase-1-mediated pyroptosis, and eventually aggravating SAKI inflammatory responses. circHIPK3 upregulated DNMT1/3a expression by competitively binding to miR-148b-3p, thus elevating the methylation level of Klotho promoter and accelerating SAKI cell senescence. Downregulation of miR-124-3p or miR-148b-3p attenuated the protective effect of circHIPK3 silencing on SAKI. Conclusion: circHIPK3 aggravated SAKI inflammatory responses via miR-124-3p/KLF6 and accelerated SAKI cell senescence via miR-148b-3p/DNMT1/3a.

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Section: Discussionsupporting

confidence: 70%

“…Previous studies have elucidated that miR-124-3p, which can bind to circHIPK3, is poorly expressed in kidney injury [16, 36]. Next, the downstream genes of miR-124-3p were predicted, among which KLF6 is upregulated in kidney injury [37, 38]. Based on the binding sites between circHIPK3 and miR-124-3p, and miR-124-3p and KLF6 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Mechanism of circHIPK3-miRNA-124-3p/miRNA-148b-3p-Mediated Inflammatory Responses and Cell Senescence in Candida albicans-Induced Septic Acute Kidney Injury

Han

Zhang

et al. 2022

Gerontology

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“…26 KLF6 is highly expressed in kidney ischemia-reperfusion (IR) injury and can promote inflammation in acute kidney injury (AKI). 27 In this study, we down-regulated the expression of KLF6 in LPS-induced A549 cells and observed that down-regulated KLF6 could improve the viability, reduce the inflammatory response, and decrease the apoptosis of LPS-induced A549 cells.…”

Section: Cyr61 Overexpression Reversed the Inhibitory Effect Of Inter...mentioning

confidence: 78%

Inhibition of KLF6 reduces the inflammation and apoptosis of type II alveolar epithelial cells in acute lung injury

Chen

Jia

2022

Allergol Immunopathol

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Background: The development of acute lung injury (ALI) into a severe stage leads to acute respi-ratory distress syndrome (ARDS). The morbidity and mortality of ALI and ARDS are very high. Objective: This study is aimed to explore the effect of Krüppel-like factor 6 (KLF6) on lipopoly-saccharide (LPS)-induced type II alveolar epithelial cells in ALI by interacting with cysteine-rich angiogenic inducer 61 (CYR61). Material and Methods: ALI mice model and LPS-induced type II alveolar epithelial cells were conducted to simulate ALI in vivo and in vitro. The messenger RNA (mRNA) and protein expres-sion of KLF6 in lung tissues were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. Pathological changes in lung tissues were observed by hematoxylin and eosin (H&E) staining. The viability and KLF6 expression of A549 cells treated with different concentrations of LPS were detected by cell counting kit-8 (CCK-8) assay, RT-qPCR, and Western blot analysis. After indicated treatment, the viability and apoptosis of A549 cells were analyzed by CCK-8 and TUNEL assays, and the inflammation factors of A549 cells were detected by Enzyme-linked-immunosorbent serologic assay, RT-qPCR, and Western blot analysis. The combination of KLF6 and CYR61 was determined by chromatin immunoprecipitation (ChIP)-PCR and dual-luciferase reporter assay. Results: KLF6 expression was increased in lung tissues of ALI mice and LPS-induced A549 cells. Interference with KLF6 improved the viability, reduced the inflammatory damage, and promoted the apoptosis of LPS-induced A549 cells. In addition, KLF6 could bind to CYR61. Interference with KLF6 could decrease CYR61 expression in LPS-induced A549 cells. LPS also enhanced the TLR4/MYD88 signaling pathway, which was reversed by KLF6 interference. The above phenomena in LPS-induced A549 cells transfected with Si-KLF6 could be reversed by overexpression of CYR61. Conclusion: Inhibition of KLF6 promoted the viability and reduced the inflammation and apop-tosis of LPS-induced A549 cells, which was reversed by CYR61.

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“…It is known that KLF15 is a member of the KLFs, which are a group of zinc-finger DNA-binding transcription factors involved in various biological processes, including cell differentiation, metabolism, inflammation, apoptosis, mitochondrial biogenesis and DNA repair [ 23 ]. Emerging evidence has demonstrated that KLFs also regulate key physiological and pathological processes in the kidney [ 24 ], some of them have been considered as early diagnosis biomarkers or therapeutic targets in AKI [ 25 ] and chronic kidney diseases [ 26 ]. Among the KLF family members, KLF15 is widely distributed in the glomeruli and in the proximal tubule.…”

Section: Discussionmentioning

confidence: 99%

Diacylglycerol kinase epsilon protects against renal ischemia/reperfusion injury in mice through Krüppel-like factor 15/klotho pathway

et al. 2022

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Although recent studies have indicated that mutations in the gene encoding diacylglycerol kinase epsilon (DGKE) result in some proteinuria related hereditary kidney diseases, the DGKE expression pattern in the kidney and its contribution to acute kidney injury (AKI) remain unknown. Therefore, the present study was designed to detect the role of DGKE in mice with AKI. DGKE expression was time-dependently altered in the kidneys of mice with renal ischemia/reperfusion injury (IRI). Compared with wild-type (WT) mice, DGKE- overexpressing mice ( Rosa26-Dgke +/+ ) exhibited protective effects against renal IRI, including reduced serum creatinine, blood urea concentration, tubular cell death and inflammatory responses as well as improved morphological injuries. Consistently, in vitro , DGKE overexpression in human renal proximal tubule (HK-2) cells also protected against oxygen-glucose deprivation (OGD)/reoxygenation-induced cell death. Mechanistically, DGKE regulated Klotho expression, at least partly via the transcription factor Krüppel-like factor (KLF) 15. Moreover, a significant reduction in DGKE was also found in kidneys from patients with ischemia-associated acute tubular necrosis (ATN). Collectively, our studies demonstrate that DGKE protects against AKI in mice at least partly through KLF15/Klotho signaling pathway, indicating that DGKE may present an innovative therapeutic strategy for treating patients with AKI.

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Role of promoting inflammation of Krüppel-like factor 6 in acute kidney injury

Cited by 12 publications

References 48 publications

Mechanism of circHIPK3-miRNA-124-3p/miRNA-148b-3p-Mediated Inflammatory Responses and Cell Senescence in <b><i>Candida albicans</i></b>-Induced Septic Acute Kidney Injury

Mechanism of circHIPK3-miRNA-124-3p/miRNA-148b-3p-Mediated Inflammatory Responses and Cell Senescence in <b><i>Candida albicans</i></b>-Induced Septic Acute Kidney Injury

Inhibition of KLF6 reduces the inflammation and apoptosis of type II alveolar epithelial cells in acute lung injury

Diacylglycerol kinase epsilon protects against renal ischemia/reperfusion injury in mice through Krüppel-like factor 15/klotho pathway

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