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

Lin, Jun‐Tao; Cheng, Antony S.; Cheng, Kai Yuan; Deng, Qingwei; Zhang, Shouzan; Lan, Zehao; Wang, Weidong; Chen, Jianghua

doi:10.3390/ijms21197057

Cited by 96 publications

(67 citation statements)

References 132 publications

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“…Uncontrolled mitochondria dysfunction eventually leads to the activation of the intrinsic cell death pathway and cell death ( 47 , 48 ). Cell death may present in various forms, including apoptosis, autophagic cell death, pyroptosis ( 49 ).…”

Section: Mitochondrial Dysfunctionmentioning

confidence: 99%

Update on the Mechanisms of Tubular Cell Injury in Diabetic Kidney Disease

Chang

Yan

et al. 2021

Front. Med.

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Increasing evidence supports a role of proximal tubular (PT) injury in the progression of diabetic kidney disease (DKD), in patients with or without proteinuria. Research on the mechanisms of the PT injury in DKD could help us to identify potential new biomarkers and drug targets for DKD. A high glucose transport state and mismatched local hypoxia in the PT of diabetes patients may be the initiating factors causing PT injury. Other mechanism such as mitochondrial dysfunction, reactive oxygen species (ROS) overproduction, ER stress, and deficiency of autophagy interact with each other leading to more PT injury by forming a vicious circle. PT injury eventually leads to the development of tubulointerstitial inflammation and fibrosis in DKD. Many downstream signaling pathways have been demonstrated to mediate these diseased processes. This review focuses mostly on the novel mechanisms of proximal renal tubular injury in DKD and we believe such review could help us to better understand the pathogenesis of DKD and identify potential new therapies for this disease.

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Section: Mitochondrial Dysfunctionmentioning

confidence: 99%

Update on the Mechanisms of Tubular Cell Injury in Diabetic Kidney Disease

Chang

Yan

et al. 2021

Front. Med.

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“…Recent research has demonstrated that the NLRP3 inflammasome plays a vital role in podocyte injury under high glucose (HG) conditions (Hou et al, 2020). Pyroptosis is a newly discovered lytic form of programmed cell death that has been shown to play a critical role in DKD (Lin et al, 2020). Pyroptosis involves cell swelling, rupture, the secretion of cell contents, and dramatic proinflammatory effects.…”

Section: Introductionmentioning

confidence: 99%

Total Flavones of Abelmoschus manihot Ameliorates Podocyte Pyroptosis and Injury in High Glucose Conditions by Targeting METTL3-Dependent m6A Modification-Mediated NLRP3-Inflammasome Activation and PTEN/PI3K/Akt Signaling

Liu

et al. 2021

Front. Pharmacol.

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Background: The total flavones of Abelmoschus manihot (TFA), a compound that is extracted from Abelmoschus manihot, has been widely used in China to reduce podocyte injury in diabetic kidney disease (DKD). However, the mechanisms underlying the therapeutic action of this compound have yet to be elucidated. Podocyte pyroptosis is characterized by activation of the NLRP3 inflammasome and plays an important role in inflammation-mediated diabetic kidneys. Regulation of the PTEN/PI3K/Akt pathway is an effective strategy for improving podocyte damage in DKD. Previous research has also shown that N6-methyladenosine (m6A) modification is involved in DKD and that m6A-modified PTEN regulates the PI3K/Akt pathway. In this study, we investigated whether TFA alleviates podocyte pyroptosis and injury by targeting m6A modification-mediated NLRP3-inflammasome activation and PTEN/PI3K/Akt signaling.Methods: We used MPC-5 cells under high glucose (HG) conditions to investigate the key molecules that are involved in podocyte pyroptosis and injury, including activation of the NLRP3 inflammasome and the PTEN/PI3K/Akt pathway. We detected alterations in the levels of three methyltransferases that are involved in m6A modification. We also investigated changes in the levels of these key molecules in podocytes with the overexpression or knockdown of methyltransferase-like (METTL)3.Results: Analysis showed that TFA and MCC950 protected podocytes against HG-induced pyroptosis and injury by reducing the protein expression levels of gasdermin D, interleukin-1β, and interleukin-18, and by increasing the protein expression levels of nephrin, ZO-1, WT1 and podocalyxin. TFA and 740Y-P inhibited activation of the NLRP3 inflammasome via the PI3K/Akt pathway by inhibiting the protein levels of NIMA-related kinase7, NLRP3, ASC, and caspase-1, and by increasing the protein expression levels of p-PI3K and p-Akt. TFA improved pyroptosis and injury in HG-stimulated podocytes by regulating METTL3-dependent m6A modification.Conclusion: Collectively, our data indicated that TFA could ameliorate pyroptosis and injury in podocytes under HG conditions by adjusting METTL3-dependent m6A modification and regulating NLRP3-inflammasome activation and PTEN/PI3K/Akt signaling. This study provides a better understanding of how TFA can protect podocytes in DKD.

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“…Piperine reportedly protected macrophages from pyroptosis in a mouse model intraperitoneally infected with Escherichia coli 33 . In a previous study, it was reported that pyroptosis plays a central role in many diseases, including osteoarthritis 49 , kidney diseases 50 , rheumatoid arthritis 51 , and COVID-19 52 . Therefore, we suspected that piperine may suppress pyroptosis in SCI.…”

Section: Discussionmentioning

confidence: 99%

Piperine Attenuates the Inflammatory Response, Oxidative Stress and Pyroptosis to Facilitate Recovery After Spinal Cord Injury via Autophagy Enhancement

Zhang

Huang

et al. 2021

Preprint

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Background: Spinal cord injury (SCI) is a serious injury that can lead to irreversible motor dysfunction and subsequently result in disability and even death. Due to its complicated pathogenic mechanism, there are no effective drug treatments. Piperine, a natural active alkaloid extracted from black pepper, suppressed inflammation in a previous study. The aim of this study was to investigate the therapeutic effect of piperine in a spinal cord injury model.Methods: Spinal cord injury was induced in C57BL/6 mice by clamping the spinal cord with a vascular clip (15 g force; Oscar) for 1 min. Eighty mice were divided randomly into the following four groups: The Sham group (n = 20), the SCI+Vehicle group (n = 20), the SCI+ Piperine group (n = 20), and the SCI+ Piperine+3MA group (n = 20). Before SCI and every 2 days post-SCI, evaluations of the Basso mouse scale (BMS) were performed. On day 14 after SCI, inclined plane tests and footprint analyses were performed. On postoperative day 3, the spinal cord was harvested to assess pyroptosis, reactive oxygen species (ROS), inflammation, and autophagy. Qualitative or quantitative analysis of the components of these potential mechanisms was performed by Western blotting (WB), immunofluorescence (IF), quantitative real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA).Results: Piperine enhanced the functional recovery of spinal cord injury. Additionally, piperine inhibited inflammation, attenuated oxidative stress and pyroptosis, and activated autophagy. However, the effects of piperine on the functional recovery of SCI, ROS-mediated autophagy, inflammation and pyroptosis were reversed by the inhibition of autophagy.Conclusions: Our experiments demonstrated that piperine facilitated the functional recovery of spinal cord injury by inhibiting the inflammatory response, oxidative stress and pyroptosis, which are mediated by the activation of autophagy.

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

Cited by 96 publications

References 132 publications

Update on the Mechanisms of Tubular Cell Injury in Diabetic Kidney Disease

Update on the Mechanisms of Tubular Cell Injury in Diabetic Kidney Disease

Total Flavones of Abelmoschus manihot Ameliorates Podocyte Pyroptosis and Injury in High Glucose Conditions by Targeting METTL3-Dependent m6A Modification-Mediated NLRP3-Inflammasome Activation and PTEN/PI3K/Akt Signaling

Piperine Attenuates the Inflammatory Response, Oxidative Stress and Pyroptosis to Facilitate Recovery After Spinal Cord Injury via Autophagy Enhancement

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