Inhibition of Autophagy Attenuated Ethylene Glycol Induced Crystals Deposition and Renal Injury in a Rat Model of Nephrolithiasis

Liu, Yunlong; Liu, Quan; Xiang, Wu; He, Ziqi; Li, Derong; Guan, Xiangdong; Zhou, Tao; Deng, Yaoliang

doi:10.1159/000487678

Cited by 21 publications

(16 citation statements)

References 36 publications

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“…Consistent with our results, H19 has been recognized as an inflammatory regulator that triggers the immune response and induces tissue injury [10], [11], [12]. In addition, a recent study reported that autophagy was an important regulator in the formation and progression of kidney stone disease, and the inhibition of autophagy could decrease kidney injury and crystal deposition in an ethylene glycol-induced rat model of nephrolithiasis [22]. H19 was also reported to be involved in the regulation of autophagy.…”

Section: Discussionsupporting

confidence: 90%

H19 promote calcium oxalate nephrocalcinosis-induced renal tubular epithelial cell injury via a ceRNA pathway

Liu

Yang

et al. 2019

EBioMedicine

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BackgroundIntrarenal calcium oxalate (CaOx) crystals induce inflammation and kidney tubular cell injury, which are processes that involve TLR4/NF-κB signalling. A recent genome-wide gene expression profile analysis of Randall's plaques in CaOx stone patients revealed that the expression of the long noncoding RNA H19 was significantly upregulated. However, to date, its role in kidney CaOx stones has not been reported.MethodA Gene Expression Omnibus (GEO) dataset was utilized to analyse gene expression profiles. Luciferase reporter, Western blotting, qRT-PCR, immunofluorescence staining and reactive oxygen species (ROS) assays were employed to study the molecular mechanism of HMGB1/TLR4/NF-κB regulation by H19 and miR-216b. In vitro and in vivo assays were performed to further confirm the proinflammatory and prooxidative stress effects.FindingH19 expression was significantly increased and positively correlated with the expression levels of HMGB1, TLR4 and NF-κB in Randall's plaques and glyoxylate-induced CaOx nephrocalcinosis mouse models. H19 interacted with miR-216b and suppressed its expression. Additionally, miR-216b inhibited HMGB1 expression by directly binding its 3′-untranslated region. Moreover, H19 downregulation inhibited HMGB1, TLR4 and NF-κB expression and suppressed CaOx nephrocalcinosis-induced renal tubular epithelial cell injury, NADPH oxidase, and oxidative stress in vivo and in vitro. Interestingly, miR-216b inhibition partially reversed the inhibitory effect of H19 knockdown on HMGB1 expression.InterpretationWe determined that H19 might serve as a facilitator in the process of CaOx nephrocalcinosis-induced oxidative stress and renal tubular epithelial cell injury, and we revealed that the interaction between H19 and miR-216b could exert its effect via the HMGB1/TLR4/NF-κB pathway.FundingThis work was supported by the (Nos. 8196030190, 8190033175, 81370805, 81470935, 81900645, 81500534, and 81602236).

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Section: Discussionsupporting

confidence: 90%

H19 promote calcium oxalate nephrocalcinosis-induced renal tubular epithelial cell injury via a ceRNA pathway

Liu

Yang

et al. 2019

EBioMedicine

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“…Tubule calcium reabsorption in patients with hypercalciuria is reduced compared with that of patients with normal calcium excretion [3]. Emerging evidence indicates that autophagy and inflammatory responses are related to the formation of CaOx nephrolithiasis [4, 5]. Our previous study demonstrated that hypercalciuria may result in increased urinary excretion of various inflammatory cytokines, such as high-mobility group box-1 (HMGB1) and monocyte chemotactic protein-1 [6].…”

Section: Introductionmentioning

confidence: 99%

Ethyl Pyruvate Attenuates CaCl<sub>2</sub>-Induced Tubular Epithelial Cell Injury by Inhibiting Autophagy and Inflammatory Responses

Zhao¹,

Cheng²,

Li³

et al. 2018

Kidney Blood Press Res

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Background/Aims: Nephrolithiasis is one of the most prevalent diseases of the urinary system. Approximately 80% of human kidney stones are composed of calcium oxalate (CaOx), and hypercalciuria is one of the most common metabolic disorders. Emerging evidence indicates that autophagy and inflammatory responses are related to the formation of CaOx nephrolithiasis. However, the roles of autophagy and inflammation in patients with hypercalciuria remain unclear. Ethyl pyruvate (EP) displays protective effects in experimental models of many illnesses. In this study, we investigated the protective effects of EP in vitro through its inhibition of autophagy and inflammatory responses after CaCl₂-induced tubular epithelial cell injury. Methods: First, we cultured human tubular epithelial (HK-2) cells in the presence of various concentrations of CaCl₂ (0, 0.1, 0.25, 0.5, 1.0, 1.5, and 2.0 mg/ml) for 12 h and EP (0, 1.0, 2.5, 5.0, and 10.0 mM) for 2 h to select the optimum concentration using the Cell Counting Kit-8 assay and lactate dehydrogenase (LDH) assay. Cells in culture were stimulated with CaCl₂ (1.0 mg/ml, 12 h) with or without EP pretreatment (2.5 mM, 2 h). After the exposure, we detected the expression of inflammation-related proteins using an enzyme-linked immunosorbent assay and Western blot analysis. Finally, the levels of autophagy-related proteins were determined through Western blot analysis, and the number of GFP-LC3 dots and autophagic vacuoles was detected under confocal microscopy. Results: With the use of the Cell Counting Kit-8 assay and the LDH assay, we identified the optimum concentration for CaCl₂ (1.0 mg/ml) treatment and EP pretreatment (2.5 mM). Our research indicated that CaCl₂ can induce autophagy and inflammatory responses in HK-2 cells. Furthermore, treatment with EP prior to CaCl₂ stimulation attenuated HK-2 cell injury by inhibiting autophagy and inflammation. Conclusion: Our results provide evidence that EP attenuates CaCl₂-induced injury of HK-2 cells by downregulating the expression of inflammation and autophagy proteins that may be associated with the inhibition of the high-mobility group box-1 (HMGB1)/toll-like receptor 4 (TLR4)/NF-κB pathway and the competitive interaction with Beclin-1 of HMGB1.

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“…Previous evidence showed that the level of autophagy in patients with CaOx kidney stones was significantly higher than that in healthy controls and CaOx crystals promoted the production of ROS in RTEC, which mediated the activation of autophagy [ 9 , 10 ]. On the contrary, the inhibition of autophagy effectively attenuated CaOx crystals-induced oxidative stress damage, mitochondrial injury, urinary oxalate excretion, renal crystal deposition, and finally inhibited the formation of CaOx crystals in rat kidneys [ 9 – 11 ].…”

Section: Introductionmentioning

confidence: 99%

Taurine suppresses ROS-dependent autophagy via activating Akt/mTOR signaling pathway in calcium oxalate crystals-induced renal tubular epithelial cell injury

Sun

Dai

Jin

et al. 2020

Aging

Self Cite

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Oxidative stress and autophagy are the key promoters of calcium oxalate (CaOx) nephrolithiasis. Taurine is an antioxidant that plays a protective role in the pathogenesis of kidney disease. Previous studies found that taurine suppressed cellular oxidative stress, and inhibited autophagy activation. However, the effect of taurine on CaOx kidney stone formation remains unknown. In the present work, we explored the regulatory effects of taurine on CaOx crystals-induced HK-2 cell injury. Results showed that pretreatment with taurine significantly enhanced the viability of HK-2 cells and ameliorated kidney tissue injury induced by CaOx crystals. Taurine also markedly reduced the levels of inflammatory cytokines, apoptosis, and CaOx crystals deposition. Furthermore, we observed that taurine supplementation alleviated CaOx crystals-induced autophagy. Mechanism studies showed that taurine reduced oxidative stress via increasing SOD activity, reducing MDA concentration, alleviating mitochondrial oxidative injury, and decreasing the production of intracellular ROS. Taurine treatment also effectively activated Akt/mTOR signaling pathway in CaOx crystals-induced HK-2 cells both in vitro and in vivo . In summary, the current study shows that taurine inhibits ROS-dependent autophagy via activating Akt/mTOR signaling pathway in CaOx crystals-induced HK-2 cell and kidney injury, suggesting that taurine may serve as an effective therapeutic agent for the treatment of CaOx nephrolithiasis.

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Inhibition of Autophagy Attenuated Ethylene Glycol Induced Crystals Deposition and Renal Injury in a Rat Model of Nephrolithiasis

Cited by 21 publications

References 36 publications

H19 promote calcium oxalate nephrocalcinosis-induced renal tubular epithelial cell injury via a ceRNA pathway

H19 promote calcium oxalate nephrocalcinosis-induced renal tubular epithelial cell injury via a ceRNA pathway

Ethyl Pyruvate Attenuates CaCl<sub>2</sub>-Induced Tubular Epithelial Cell Injury by Inhibiting Autophagy and Inflammatory Responses

Taurine suppresses ROS-dependent autophagy via activating Akt/mTOR signaling pathway in calcium oxalate crystals-induced renal tubular epithelial cell injury

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