Podocyte-specific Nlrp3 inflammasome activation promotes diabetic kidney disease

Shahzad, Khurrum; Fatima, Sameen; Khawaja, Hamzah; Elwakiel, Ahmed; Gadi, Ihsan; Ambreen, Saira; Zimmermann, S; Mertens, Peter R.; Biemann, Ronald; Isermann, Berend

doi:10.1016/j.kint.2022.06.010

Cited by 69 publications

(36 citation statements)

References 52 publications

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“…Pyroptosis is another inflammatory cell death mechanism that is strongly dependent on NLRP3, gasdermin, and caspase-1 activation, leading to cleavage of IL-1β and cellular death ( 136 , 137 ). Inflammasome-mediated cell death has been shown to contribute to DKD by several groups ( 138 , 139 ). More severe damage can lead to the release of mitochondrial DNA (mtDNA) into the cytosol.…”

Section: Proximal Tubule Cell Pathology Correlates With Gfr Changesmentioning

confidence: 99%

Molecular pathways that drive diabetic kidney disease

Mohandes¹,

Doke²,

Hu³

et al. 2023

Journal of Clinical Investigation

145

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Section: Proximal Tubule Cell Pathology Correlates With Gfr Changesmentioning

confidence: 99%

Molecular pathways that drive diabetic kidney disease

Mohandes¹,

Doke²,

Hu³

et al. 2023

Journal of Clinical Investigation

145

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“…High glucose can increase the expression of TLR4, cleaved caspase-1, GSDMD-NT, and the secretion of IL-1β and IL-18 in mice diabetic kidneys. 332,333 TLR4 inhibitor and NF-κB inhibitor partially reversed the pyroptosis induced by high glucose. 334 In podocytes stimulated by high glucose, the release of proinflammatory cytokines and chemokines, including intracellular ROS, IL-6 and IL-1β, is increased by activation of TLR4/NF-κB signaling pathway.…”

Section: Pyroptosis and Diabetesmentioning

confidence: 92%

“…The cause of hyperglycemia associated with diabetic nephropathy (DN) is inadequate insulin secretion or insulin resistance, which leads to hypoxia and excessive production of inflammatory cytokines. High glucose can increase the expression of TLR4, cleaved caspase‐1, GSDMD‐NT, and the secretion of IL‐1β and IL‐18 in mice diabetic kidneys 332,333 . TLR4 inhibitor and NF‐κB inhibitor partially reversed the pyroptosis induced by high glucose 334 .…”

Section: Pyroptosis and Metabolic Diseasesmentioning

confidence: 96%

Role of pyroptosis in the pathogenesis and treatment of diseases

Jin

Liu

et al. 2023

MedComm

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Programmed cell death (PCD) is regarded as a pathological form of cell death with an intracellular program mediated, which plays a pivotal role in maintaining homeostasis and embryonic development. Pyroptosis is a new paradigm of PCD, which has received increasing attention due to its close association with immunity and disease. Pyroptosis is a form of inflammatory cell death mediated by gasdermin that promotes the release of proinflammatory cytokines and contents induced by inflammasome activation. Recently, increasing evidence in studies shows that pyroptosis has a crucial role in inflammatory conditions like cardiovascular diseases (CVDs), cancer, neurological diseases (NDs), and metabolic diseases (MDs), suggesting that targeting cell death is a potential intervention for the treatment of these inflammatory diseases. Based on this, the review aims to identify the molecular mechanisms and signaling pathways related to pyroptosis activation and summarizes the current insights into the complicated relationship between pyroptosis and multiple human inflammatory diseases (CVDs, cancer, NDs, and MDs). We also discuss a promising novel strategy and method for treating these inflammatory diseases by targeting pyroptosis and focus on the pyroptosis pathway application in clinics.

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“…Using primary renal tubular epithelial cells and unilateral ureteral obstruction (UUO) mice, a recent study demonstrated that peroxisomal proliferator-γ coactivator-1α (PGC-1α) ameliorates NLRP3 inflammasome-associated renal fibrosis via the modulation of mitochondrial dynamics [ 58 ]. NLRP3 activation also contributes to DKD progression as shown in a study demonstrating that podocyte-specific Nlrp3 or caspase-1 deficiency resulted in protection from DKD [ 59 ]. In contrast, another group reported that using an NLRP3-specific inhibitor, MCC950, did not confer renoprotective effects using streptozotocin-induced diabetic mice as it did not reduce renal inflammation (glomerular accumulation of CD68 positive cells), mesangial expansion and glomerulosclerosis [ 60 ].…”

Section: Mitochondrial Regulation Of Inflammationmentioning

confidence: 99%

Mitochondrial Contribution to Inflammation in Diabetic Kidney Disease

Mitrofanova

Fontanella

Burke

et al. 2022

Cells

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Diabetes is the leading cause of chronic kidney disease worldwide. Despite the burden, the factors contributing to the development and progression of diabetic kidney disease (DKD) remain to be fully elucidated. In recent years, increasing evidence suggests that mitochondrial dysfunction is a pathological mediator in DKD as the kidney is a highly metabolic organ rich in mitochondria. Furthermore, low grade chronic inflammation also contributes to the progression of DKD, and several inflammatory biomarkers have been reported as prognostic markers to risk-stratify patients for disease progression and all-cause mortality. Interestingly, the term “sterile inflammation” appears to be used in the context of DKD describing the development of intracellular inflammation in the absence of bacterial or viral pathogens. Therefore, a link between mitochondrial dysfunction and inflammation in DKD exists and is a hot topic in both basic research and clinical investigations. This review summarizes how mitochondria contribute to sterile inflammation in renal cells in DKD.

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Podocyte-specific Nlrp3 inflammasome activation promotes diabetic kidney disease

Cited by 69 publications

References 52 publications

Molecular pathways that drive diabetic kidney disease

Molecular pathways that drive diabetic kidney disease

Role of pyroptosis in the pathogenesis and treatment of diseases

Mitochondrial Contribution to Inflammation in Diabetic Kidney Disease

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