Angiotensin II Stimulates the NLRP3 Inflammasome to Induce Podocyte Injury and Mitochondrial Dysfunction

Zhao, Min; Bai, Mei; Ding, Guofu; Zhang, Yue; Huang, Songming; Jia, Zhanjun; Zhang, Aihua

doi:10.1159/000488242

Cited by 60 publications

(54 citation statements)

References 32 publications

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“…Additionally, the NLRP3 gene is known to be associated with many non-infectious diseases of the nervous system, such as spinal cord injury and X-linked adrenoleukodystrophy (25,26). NLRP3 is also involved in the innate immune response of the body (27). These observations suggest that NLRP3 and inflammatory factors are involved in the occurrence and development of epilepsy.…”

Section: Figure 4 |mentioning

confidence: 99%

The Role of NLRP3 and IL-1β in Refractory Epilepsy Brain Injury

Zhang

Chen

et al. 2020

Front. Neurol.

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The objective of this study was to investigate the roles and mechanisms of inflammatory mediators NLRP3 and IL-1β in refractory temporal epilepsy brain injury. Method: First, the brain tissue and the peripheral blood of children undergoing intractable temporal lobe epilepsy surgery were analyzed as research objects. The expression levels of NLRP3 in brain tissue and IL-1β in blood were measured. A model of temporal lobe epilepsy was established using wild-type and NLRP3 knockout 129 mice. Pilocarpine was injected intraperitoneally into the experimental group, and isovolumetric saline was injected intraperitoneally into the control group (n = 8 in each group). The expression of IL-1β in the peripheral blood, cerebral cortex, and hippocampus of mice was measured by ELISA at 3 h, 24 h, 3 days, and 7 days after modeling. Fluoro-Jade B (FJB) and TUNEL methods were used to determine necrosis and apoptosis in hippocampal neurons, respectively, and the expression of NLRP3 in the cortex was measured by immunofluorescence methods. Result: (1) The IL-1β levels in the peripheral blood of children with intractable temporal lobe epilepsy were higher than those in the control group (t = 2.813, P = 0.01). There was also a positive correlation between IL-1β expression levels and the onset time of a single convulsion in patients with refractory epilepsy (r = 0.9735, P < 0.05). The expression level of NLRP3 in the cerebral cortex of patients with refractory temporal lobe epilepsy was higher than that in the control group. (2) The expression level of NLRP3 in the hippocampus of wild-type mice increased 3 days after modeling and decreased slightly at 7 days but remained higher than that of the control group. IL-1β levels in peripheral blood were significantly higher than those in the control group at 3 days (t = 8.259, P < 0.0001). The IL-1β levels in the peripheral blood of NLRP3 knockout mice were lower than those in the wild-type group at 3 days (t = 3.481, P = 0.004). At day 7, the neuronal necrosis and apoptosis levels in the CA3 region of the hippocampus decreased. Conclusion: NLRP3 may be involved in the development of refractory temporal lobe epilepsy. Inhibiting NLRP3 may alleviate local brain injury by downregulating the IL-1β expression. The IL-1β levels in the peripheral blood of patients with refractory temporal lobe epilepsy may reflect the severity of convulsions.

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Section: Figure 4 |mentioning

confidence: 99%

The Role of NLRP3 and IL-1β in Refractory Epilepsy Brain Injury

Zhang

Chen

et al. 2020

Front. Neurol.

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“…ASC deficiency and IL-1R antagonism have blood pressure-lowering and renal anti-inflammatory effects [58,61]. Activation of the NLRP3 inflammasome regulates Ang II-induced podocyte injury by inducing mitochondrial dysfunction, and systemic deletion of NLRP3 can significantly attenuate renal injury resulting from mitochondrial dysfunction [62]. The application of aldosterone can activate NLRP3 in podocytes through oxidative stressrelated mechanisms.…”

Section: Lupus Nephritismentioning

confidence: 99%

Research Progress on the Role of Inflammasomes in Kidney Disease

Chi

Geng

Liu

et al. 2020

Mediators of Inflammation

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Inflammasomes are multimeric complexes composed of cytoplasmic sensors, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC or PYCARD), and procaspase-1 and play roles in regulating caspase-dependent inflammation and cell death. Inflammasomes are assembled by sensing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) and initiate inflammatory responses by activating caspase-1. Activated caspase-1 promotes the release of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18 and eventually induces pyroptosis. Inflammasomes are closely related to kidney diseases. In particular, the NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome has been shown to cause acute and chronic kidney diseases by regulating canonical and noncanonical mechanisms of inflammation. Small-molecule inhibitors that target NLRP3 and other components of the inflammasome are potential options for the treatment of kidney-related diseases such as diabetic nephropathy. This article will focus on the research progress on inflammasomes and the key pathogenic roles of inflammasomes in the development and progression of kidney diseases and explore the potential of this intracellular inflammation to further prevent or block the development of the kidney disease.

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“…Recent studies have shown that Ang II can activate and/or trigger various cellular events (e.g. oxidative stress and reactive oxygen species overproduction, endoplasmic reticulum stress, autophagy and mitochondrial dysfunction), thus resulting in cytoskeletal rearrangement and podocyte apoptosis [4][5][6][7][8][9]. Notably, NADPH oxidase (Nox) plays a critical role in driving reactive oxygen species (ROS) production.…”

Section: Introductionmentioning

confidence: 99%

Angiotensin II promotes podocyte injury by activating Arf6-Erk1/2-Nox4 signaling pathway

Che

Gao

et al. 2020

PLoS ONE

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Angiotensin II (Ang II) is a key contributor to glomerular disease by predominantly resulting in podocyte injury, whereas the underlying molecular mechanisms has not been fully understood. This study aimed to investigate if and how ADP-ribosylation factor 6 (Arf6), a small GTP-binding protein, involves Ang II-induced cellular injury in cultured human podocytes. Cellular injury was evaluated with caspase 3 activity, reactive oxygen species (ROS) level and TUNEL assay. Arf6 activity was measured using an Arf6-GTP Pull-Down Assay. Ang II significantly enhanced Arf6 expressions accompanied by increase of Arf6-GTP. The TUNEL-positive cells as well as activated caspase 3, NADPH oxidase 4 protein (Nox4) and ROS levels were dramatically increased in Ang II-treated podocytes, which was prevented by secinH3, an Arf6 activity inhibitor. Induction of ROS by Ang II was inhibited in podocytes with Nox4 knockdown. Ang II-induced elevation of Nox4 and ROS was prevented by Arf6 knockdown. Phpspho-Erk1/2 Thr202/Tyr204 levels were upregulated remarkably following Ang II treatment, and Erk inhibitor LY3214996 significantly downregulated Nox4 expression. In addition, Ang II decreased CD2AP expression. Overexpression of CD2AP prevented Ang IIinduced upregulation of Arf6-GTP. Our data demonstrated that Ang II promotes ROS production and podocytes injury through activation of Arf6-Erk1/2-Nox4 signaling. We also provided evidence that Ang II activates Arf6 by degradation of CD2AP.

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Angiotensin II Stimulates the NLRP3 Inflammasome to Induce Podocyte Injury and Mitochondrial Dysfunction

Cited by 60 publications

References 32 publications

The Role of NLRP3 and IL-1β in Refractory Epilepsy Brain Injury

The Role of NLRP3 and IL-1β in Refractory Epilepsy Brain Injury

Research Progress on the Role of Inflammasomes in Kidney Disease

Angiotensin II promotes podocyte injury by activating Arf6-Erk1/2-Nox4 signaling pathway

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