αKlotho protein has therapeutic activity in contrast-induced acute kidney injury by limiting NLRP3 inflammasome-mediated pyroptosis and promoting autophagy

Zhu, Xuying; Li, Shu; Lin, Qisheng; Shao, Xinghua; Wu, Jinlong; Zhang, Weimin; Cai, Hong; Zhou, Wenyan; Jiang, Na; Zhang, Zhen; Shen, Jianxiao; Wang, Qin; Ni, Zhaohui

doi:10.1016/j.phrs.2021.105531

Cited by 38 publications

(23 citation statements)

References 39 publications

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“…In contrast, mice with a genetic propensity for albuminuria have increased urinary Klotho excretion [ 52 ]. The potential mechanisms of such an interaction may involve suppressing the induction of proinflammatory cytokines, protecting against podocyte injury directly in situ or by autocrine or paracrine effects [ 52 ], limiting nucleotide-binding oligomerization domain-like pyrin domain containing protein 3 inflammasome-mediated pyroptosis and promoting autophagy [ 53 ], influencing sodium/phosphate cotransporter activity and oxidative stress, further regulating vascular calcification and endothelial dysfunction [ 54 , 55 ]. These mechanisms can, in turn, crosstalk with each other.…”

Section: Discussionmentioning

confidence: 99%

Association between Serum Soluble α-Klotho and Urinary Albumin Excretion in Middle-Aged and Older US Adults: NHANES 2007–2016

Chang

Zheng

et al. 2023

JCM

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(1) Background: Preclinical and clinical studies on the anti-aging effect of α-Klotho are emerging. Urinary albumin excretion (UAE) is a well-known biomarker of kidney injury and generalized damage in the cardiovascular system. However, the potential relationship between α-Klotho and UAE is limited and controversial. This study aimed to quantify this relationship in the general middle-aged and elderly population from the National Health and Nutrition Survey (NHANES) 2007–2016. (2) Methods: Serum α-Klotho was measured by enzyme-linked immunosorbent assay. UAE was assessed by the albumin-to-creatinine ratio (ACR). After adjusting for several confounding variables, the relationship between α-Klotho and ACR was analyzed by weighted multivariable logistic regression, subgroup analysis, and interaction tests. A generalized additive model (GAM) with smooth functions using the two-piecewise linear regression model was used to examine the potential nonlinear relationship between α-Klotho and ACR. (3) Results: Among 13,584 participants aged 40–79 years, we observed an independent and significant negative correlation between α-Klotho and ACR (β = −12.22; 95% CI, −23.91, −0.53, p = 0.0448) by multivariable logistic regression analysis, especially in those with age ≥ 60 years, pulse pressure (PP) ≥ 60 mmHg, hypertension or diabetes. We further discovered the nonlinear relationship between α-Klotho and ACR by GAM, revealing the first negative and then positive correlations with an inflection point of 9.91 pg/mL between α-Klotho and ACR. (4) Conclusions: A dose-response relationship between α-Klotho and ACR was demonstrated, and the negative correlation therein indicated that α-Klotho has potential as a serum marker and prophylactic or therapeutic agent despite its metabolic and effective mechanisms needing to be further explored.

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Section: Discussionmentioning

confidence: 99%

Association between Serum Soluble α-Klotho and Urinary Albumin Excretion in Middle-Aged and Older US Adults: NHANES 2007–2016

Chang

Zheng

et al. 2023

JCM

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“… 10 Emerging studies have shown that cellular inflammation, apoptosis, and tissue damage triggered by the NLRP3 inflammasome are found during AKI development. 11 However, the mechanism of action of NLRP3 inflammasome in renal injury in CI-AKI remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Baicalin Alleviates Contrast-Induced Acute Kidney Injury Through ROS/NLRP3/Caspase-1/GSDMD Pathway-Mediated Proptosis in vitro

Li¹,

Wang²,

Huang³

et al. 2022

DDDT

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To investigate the effect of baicalin on the reactive oxygen species (ROS)/ NOD-like receptor protein 3 (NLRP3)/Caspase-1/gasdermin-D (GSDMD) inflammasome pathway and its related mechanism in regulating pyroptosis of human renal tubular epithelial cells (HK-2) induced by contrast media. Methods: Iohexol was used to act on HK-2 cells to establish a renal tubular cell pyroptosis model; and the signal pathway genes were silenced, cytokines were detected by enzyme-linked immunosorbent assay (ELISA), and cell viability, gene expression, and protein expression were evaluated by double fluorescence staining and flow cytometry. To assess the cytotoxicity caused by the contrast agent; cells were pretreated with different concentrations of baicalin; and then the cells were exposed to iohexol again, and the relevant indicators were tested again. Results: After HK-2 cells were exposed to iohexol, the NLRP3 inflammasome pathway markers NLRP3, interleukin (IL)-1β, and IL-18 mRNA levels as well as the protein expression levels of NLRP3, ASC, Caspase-1, and GSDMD were up-regulated. In addition, the effect also significantly increased the IL-18, IL-1β, lactate dehydrogenase (LDH), superoxide dismutase (SOD), malondialdehyde (MDA) release, and cellular ROS levels. The results of Annexin V-FITC/PI flow cytometry showed that the level of apoptosis was increased. However, after the intervention of baicalin, the changes in the above indexes caused by iohexol stimulation of HK-2 cells were inhibited. Conclusion: Exposure to iohexol can induce pyroptosis of HK-2 cells through the ROS/NLRP3/Caspase-1/GSDMD signaling pathway. Baicalin ameliorated iohexol-induced pyroptosis in HK-2 cells by regulating the NLRP3 inflammasome pathway.

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“… 21 , 22 , 23 Other studies reported that autophagy could be an adaptive response to protect cells under certain circumstances. 24 , 25 , 26 Baf A1 is an autophagy inhibitor that can block autophagic flux by inhibiting both the formation of autophagolysosome and the degradation of LC3‐II. To determine the role of autophagy in CRIZO‐induced hepatocyte injury, the cell survival rate was evaluated in HL‐7702 cells that were exposed to CRIZO following Baf A1 pretreatment.…”

Section: Resultsmentioning

confidence: 99%

“…It was reported that sustained autophagy activation may promote necrosis in some cellular settings 21–23 . Other studies reported that autophagy could be an adaptive response to protect cells under certain circumstances 24–26 . Baf A1 is an autophagy inhibitor that can block autophagic flux by inhibiting both the formation of autophagolysosome and the degradation of LC3‐II.…”

Section: Resultsmentioning

confidence: 99%

MgIG exerts therapeutic effects on crizotinib‐induced hepatotoxicity by limiting ROS‐mediated autophagy and pyroptosis

Wang

et al. 2022

J Cellular Molecular Medi

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Crizotinib (CRIZO) has been widely employed to treat non‐small‐cell lung cancer. However, hepatic inflammatory injury is the major toxicity of CRIZO, which limits its clinical application, and the underlying mechanism of CRIZO‐induced hepatotoxicity has not been fully explored. Herein, we used cell counting kit‐8 assay and flow cytometry to detect CRIZO‐induced cytotoxicity on human hepatocytes (HL‐7702). CRIZO significantly reduced the survival rate of hepatocytes in a dose‐dependent manner. Furthermore, the reactive oxygen species (ROS) assay kit showed that CRIZO treatment strongly increased the level of ROS. In addition, CRIZO treatment caused the appearance of balloon‐like bubbles and autophagosomes in HL‐7702 cells. Subsequently, Western blotting, quantitative real‐time PCR and ELISA assays revealed that ROS‐mediated pyroptosis and autophagy contributed to CRIZO‐induced hepatic injury. Based on the role of ROS in CRIZO‐induced hepatotoxicity, magnesium isoglycyrrhizinate (MgIG) was used as an intervention drug. MgIG activated the Nrf2/HO‐1 signalling pathway and reduced ROS level. Additionally, MgIG suppressed hepatic inflammation by inhibiting NF‐κB activity, thereby reducing CRIZO‐induced hepatotoxicity. In conclusion, CRIZO promoted autophagy activation and pyroptosis via the accumulation of ROS in HL‐7702 cells. MgIG exerts therapeutic effects on CRIZO‐induced hepatotoxicity by decreasing the level of ROS.

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αKlotho protein has therapeutic activity in contrast-induced acute kidney injury by limiting NLRP3 inflammasome-mediated pyroptosis and promoting autophagy

Cited by 38 publications

References 39 publications

Association between Serum Soluble α-Klotho and Urinary Albumin Excretion in Middle-Aged and Older US Adults: NHANES 2007–2016

Association between Serum Soluble α-Klotho and Urinary Albumin Excretion in Middle-Aged and Older US Adults: NHANES 2007–2016

Baicalin Alleviates Contrast-Induced Acute Kidney Injury Through ROS/NLRP3/Caspase-1/GSDMD Pathway-Mediated Proptosis in vitro

MgIG exerts therapeutic effects on crizotinib‐induced hepatotoxicity by limiting ROS‐mediated autophagy and pyroptosis

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