Knockdown of TLR4 attenuates high glucose-induced podocyte injury via the NALP3/ASC/Caspase-1 signaling pathway

Liu, Yang; Xu, Zhenhe; Ma, Fuzhe; Jia, Yong; Wang, Guannan

doi:10.1016/j.biopha.2018.08.134

Cited by 42 publications

(30 citation statements)

References 39 publications

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“…Moreover, TLR4/MyD88 signaling pathway plays an important role in inflammation in podocyte injury in vivo and in vitro models of DN [49–51], and TLR4 knockdown was shown to attenuate the increase in cell apoptosis in HG-induced podocyte injury [52]. TLR4 can recruit MyD88, which can also activate the NF-κB signaling pathway and cytokine production in podocyte injury [53, 54].…”

Section: Discussionmentioning

confidence: 99%

The protective effect and mechanism of catalpol on high glucose-induced podocyte injury

Chen

Liu

Shan

et al. 2019

BMC Complement Altern Med

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Background Catalpol, a natural iridoid glycoside in Rehmannia glutinosa , can alleviate proteinuria associated with diabetic nephropathy (DN), however, whether catalpol has a protective effect against podocyte injury in DN remains unclear. Methods In this study, we used a high glucose (HG)-induced podocyte injury model to evaluate the protective effect and mechanism of catalpol against HG-induced podocyte injury. Cell viability was determined by the 3-(4,5-dimethylthiazolyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. The levels of lactate dehydrogenase (LDH), superoxide dismutase (SOD) and malondialdehyde (MDA) were measured by commercial assay kits. Cell apoptosis and reactive oxygen species (ROS) were determined by using flow cytometry. Tumour necrosis factor α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) levels were determined by enzyme-linked immunosorbent assay (ELISA). The protein expression levels of B-cell lymphoma-2 (Bcl-2), Bcl2-associated x (Bax), cleaved caspase-3, nicotinamide adenine dinucleotide phosphate oxidase enzyme 4 (NOX4), toll-like receptor 4 (TLR4), myeloid differentiation primary response gene 88 (MyD88), p38 mitogen-activated protein kinase (p38 MAPK), phosphorylated p38 MAPK (p-p38 MAPK), nuclear factor kappa B inhibitor alpha (IκBα) and phosphorylated IκBα (p-IκBα) were measured by western blotting. In addition, Bcl-2, Bax, caspase-3 and nuclear factor kappa B (NF-κB) levels were determined by immunofluorescence staining. Results Catalpol significantly increased cell viability and decreased LDH release in HG-induced podocyte injury. Catalpol significantly decreased ROS generation, apoptosis, level of MDA, levels of inflammatory cytokine TNF-α, IL-1β, and IL-6 and increased SOD activity in HG-induced podocyte injury. Moreover, catalpol significantly decreased expression of cleaved caspase-3, Bax, NOX4, TLR4, MyD88, p-p38 MAPK, p-IκBα and NF-κB nuclear translocation, as well as increased Bcl-2 expression in HG-induced podocyte injury. Conclusion Catalpol can protect against podocyte injury by ameliorating apoptosis and inflammation. These protective effects may be attributed to the inhibition of NOX4, which alleviates ROS generation and suppression of the TLR4/MyD88 and p38 MAPK signaling pathways to prevent NF-κB activation. Therefore, catalpol could be a promising drug for the prevention of DN.

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Section: Discussionmentioning

confidence: 99%

The protective effect and mechanism of catalpol on high glucose-induced podocyte injury

Chen

Liu

Shan

et al. 2019

BMC Complement Altern Med

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“…TLR4 inhibition also prevents HG-induced NF-κB activation and production of inflammatory cytokines (56). Furthermore, knockdown of TLR4 prevents HG-induced oxidative stress and induction of inflammatory cytokines in cultured podocytes (57) and vascular smooth muscle cells (58). Based on these findings, a future study may explore whether L2H21 and L50H46 also reduce inflammatory signaling in models of diabetic complications through the inhibition of TLR4.…”

Section: Discussionmentioning

confidence: 90%

Curcumin Analogs Reduce Stress and Inflammation Indices in Experimental Models of Diabetes

et al. 2019

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Chronic inflammation and oxidative stress lead to a multitude of adverse cellular responses in target organs of chronic diabetic complications. Curcumin, a highly investigated phytochemical, has been shown to exhibit both anti-inflammatory and antioxidant activities. However, the clinical application of curcumin has been greatly limited due to a poor pharmacokinetic profile. To overcome these limitations, we have generated analogs of curcumin to enhance bioavailability and offer a preferable pharmacokinetic profile. Here, we explored the effects of two mono-carbonyl curcumin analogs, L2H21 and L50H46, in alleviating indices of inflammation and oxidative stress in cell culture and mouse model of diabetic complications. Our results show that L2H21 and L50H46 normalize inflammatory mediators (IL-6 and TNF-α), extracellular matrix proteins (FN and COL4α1), vasoactive factors (VEGF and ET-1) and a key transcriptional coactivator (p300) in cultured human retinal microvascular endothelial cells (HRECs) and dermal-derived microvascular endothelial cells (HMVECs) challenged with high levels of glucose. These curcumin analogs also reduced glucose-induced oxidative DNA damage as evidenced by 8-OHdG labeling. We further show that treatment of streptozotocin-induced diabetic mice with curcumin analogs prevents cardiac and renal dysfunction. The preservation of target tissue function was associated with normalization of pro-inflammatory cytokines and matrix proteins. Collectively, our results show that L2H21 and L50H46 offer the anti-inflammatory and antioxidant activities as has been reported for curcumin, and may provide a clinically applicable therapeutic option for the treatment of diabetic complications.

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“…While administration of TAK-242 (a small-molecule inhibitor of TLR4 signalling) and parthenolide (an inhibitor of NF-κB signalling) can suppress the overexpression of these pyroptosis regulatory molecules in a way. Furthermore, a prospective study has shown that the knockdown of TLR4 suppressed the assembling of NLRP3 inflammasome during HG-induced podocyte pyroptosis [ 65 ]. In vitro, the expression levels of TLR4, MyD88, NF-κBp65 and NLRP3 protein were detected by Western Blotting in HG-induced glomerular mesangial cells (HBZY-1), and all of them were overexpressed, demonstrating a causative role for TLR4/NF-κB/NLRP3 inflammasome pathway in DKD progression [ 66 ].…”

Section: Pyroptosis Regulatory Pathways In Dkdmentioning

confidence: 99%

“…Interestingly, it was found that preventing caspase-1 activation and the IL-1β maturation was the mutual mechanism for both inhibition of ASC/NLRP3 and caspase-1 [ 104 ]. Yang et al reported the NLRP3/ASC/Caspase-1 signalling pathway could be attenuated by blocking of TLR4 during podocyte pyroptosis induced by HG [ 65 ]. Previous study found that IL-17A participated in podocyte pyroptosis through ROS/NLRP3/caspase-1 signalling pathway, disrupting the morphological structure of podocytes in vitro by activating the NLRP3 inflammasome and IL-1β expression with the association and involvement of GFB disruption.…”

Section: Pathological Role Of Pyroptosis In Dkdmentioning

confidence: 99%

New Insights into the Mechanisms of Pyroptosis and Implications for Diabetic Kidney Disease

Lin

Cheng

et al. 2020

IJMS

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Pyroptosis is one special type of lytic programmed cell death, featured in cell swelling, rupture, secretion of cell contents and remarkable proinflammation effect. In the process of pyroptosis, danger signalling and cellular events are detected by inflammasome, activating caspases and cleaving Gasdermin D (GSDMD), along with the secretion of IL-18 and IL-1β. Pyroptosis can be divided into canonical pathway and non-canonical pathway, and NLRP3 inflammasome is the most important initiator. Diabetic kidney disease (DKD) is one of the most serious microvascular complications in diabetes. Current evidence reported the stimulatory role of hyperglycaemia-induced cellular stress in renal cell pyroptosis, and different signalling pathways have been shown to regulate pyroptosis initiation. Additionally, the inflammation and cellular injury caused by pyroptosis are tightly implicated in DKD progression, aggravating renal fibrosis, glomerular sclerosis and tubular injury. Some registered hypoglycaemia agents exert suppressive activity in pyroptosis regulation pathway. Latest studies also reported some potential approaches to target the pyroptosis pathway, which effectively inhibits renal cell pyroptosis and alleviates DKD in in vivo or in vitro models. Therefore, comprehensively compiling the information associated with pyroptosis regulation in DKD is the main aim of this review, and we try to provide new insights for researchers to dig out more potential therapies of DKD.

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Knockdown of TLR4 attenuates high glucose-induced podocyte injury via the NALP3/ASC/Caspase-1 signaling pathway

Cited by 42 publications

References 39 publications

The protective effect and mechanism of catalpol on high glucose-induced podocyte injury

The protective effect and mechanism of catalpol on high glucose-induced podocyte injury

Curcumin Analogs Reduce Stress and Inflammation Indices in Experimental Models of Diabetes

New Insights into the Mechanisms of Pyroptosis and Implications for Diabetic Kidney Disease

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