Mitochondrial dysfunction confers albumin-induced NLRP3 inflammasome activation and renal tubular injury

Zhuang, Yibo; Yasinta, Marchella; Hu, Caiyu; Zhao, Min; Ding, Guofu; Bai, Mei; Yang, Lu; Ni, Jiajia; Wang, Rong; Jia, Zhanjun; Huang, Songming; Zhang, Aihua

doi:10.1152/ajprenal.00203.2014

Cited by 72 publications

(63 citation statements)

References 23 publications

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“…They further investigated the mechanism and found that the endocytosis of ultrafiltered albumin in tubules might induce endoplasmic reticulum stress, which plays an important role in NLRP3 inflammasome activation. Meanwhile, our study showed that the NLRP3 inflammasome/caspase-1/mitochondria axis mediated the mouse proximal tubular cell defect [32], which might be the mechanism of the mouse proximal tubular cell tight junction injury by albumin [33]. In albumin-overloaded mice, we observed severe tubular structure damage, cell apoptosis and epithelial cell phenotype transition, as well as mitochondrial dysfunction.…”

Section: Inflammasome and Chronic Kidney Diseasementioning

confidence: 99%

Inflammasomes in the Pathophysiology of Kidney Diseases

2015

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Background: The inflammasome is a complex of proteins in the cytoplasm that consists of three main components: a sensor protein (receptor), an adapter protein and caspase-1. Inflammasomes are the critical components of innate immunity and have been gradually recognized as a critical mediator in various autoimmune diseases; also, their role in chronic kidney disease and acute kidney injury has been gradually accepted. Summary: Inflammasomes triggered by infectious or sterile injuries transfer proinflammatory mediators into mature ones through innate danger-signaling platforms. Information on inflammasomes in kidney disease will help to uncover the underlying mechanisms of nephropathy and provide novel therapeutic targets in the future. Key Messages: The inflammasomes can be activated by a series of exogenous and endogenous stimuli, including pathogen-and danger-associated molecular patterns released from or caused by damaged cells. The NACHT, LRR and PYD domain-containing protein 3 (NLRP3) in the kidney exerts its effect not only by the ‘canonical' pathway of IL-1β and IL-18 secretion but also by ‘noncanonical' pathways, such as tumor growth factor-β signaling, epithelial-mesenchymal transition and fibrosis. In both clinical and experimental data, the NLRP3 inflammasome was reported to be involved in the pathogenesis of chronic kidney disease and acute kidney injury. However, the underlying mechanisms are not fully understood. Therapies targeting the activation of the NLRP3 inflammasome or blocking its downstream effectors appear attractive for the pursuit of neuropathy treatments.

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Section: Inflammasome and Chronic Kidney Diseasementioning

confidence: 99%

Inflammasomes in the Pathophysiology of Kidney Diseases

2015

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“…Based on a previous study [12], we investigated the effects of SS-31 on the change in mtDNA copy number, ATP synthases, and the release of cytosolic Cyt C three days post-injury to analyze mitochondrial dysfunction. SCI induced significant abnormalities in mitochondrial function, as shown by the reduction in mtDNA copy number (1.0 ± 0.12, P=0.007, Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, mitochondria are a major source of reactive oxygen species (ROS) and contribute to cell signal transduction [12]. Mitochondrial dysfunction leads to an increase in ROS production, mitochondrial DNA damage (copy number reduction and mutation), disorders in oxidative phosphorylation of the mitochondrial respiratory chain, and the reduction of ATP production [33].…”

Section: Discussionmentioning

confidence: 99%

“…Mitochondrial dysfunction leads to increased ROS production, mitochondrial DNA damage (copy number reduction and mutation), and disorders of oxidative phosphorylation of the mitochondrial respiratory chain [12, 13]. Previous reports have shown mitochondrial dysfunction, which is important for energy metabolism, inflammatory responses, oxidative stress, the intrinsic apoptotic pathway, plays a substantial role in lung injury [14, 15].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, mitochondrial DNA damage initiates lung injury and multi-organ system failure in rats following intra-tracheal Pseudomonas aeruginosa administration [16]. In addition, mitochondrial ROS are considered to be important factors in NOD-like receptor protein-3 (NLRP3) inflammasome activation [12]. Therefore, regulation of mitochondrial dysfunction is an important strategy for the treatment of SCI-induced lung injury.…”

Section: Introductionmentioning

confidence: 99%

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Mitochondria Targeted Peptide Attenuates Mitochondrial Dysfunction, Controls Inflammation and Protects Against Spinal Cord Injury-Induced Lung Injury

Zhu¹,

Li²,

He³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Spinal cord injury (SCI) is a common and devastating disease, which results in systemic inflammatory response syndrome and secondary lung injury. Mitochondrial dysfunction and inflammation are closely related to lung injury in diverse disease models. No studies have demonstrated the effects of mitochondrial targeted peptide SS-31 in a mouse model of SCI-induced lung injury. Methods: Immediately after injury, mice in the treatment groups received a daily, single-dose intraperitoneal injection of SS-31 and for the next 2 days. The sham and SCI groups also received a daily single dose of vehicle (DMSO and 0.9% NaCl, 1: 3). The lung tissue of mice was examined after SCI, and tissue damage, apoptosis, inflammation, and mitochondrial dysfunction were recorded. Results: SS-31 treatment attenuated lung edema and tissue damage. Furthermore, SS-31 treatment reduced apoptosis of alveolar type II cells, the number of total macrophages and M1 macrophages, and neutrophil infiltration. Moreover, SS-31 treatment attenuated reactive oxygen species levels, reversed mitochondrial dysfunction and inhibited NLRP3 inflammasome activation. Conclusions: Collectively, our results demonstrate that SS-31 attenuates mitochondrial dysfunction, controls inflammatory responses, and alleviates the severity of lung damage in a mouse model of SCI-induced lung injury.

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Podocyte Activation of NLRP3 Inflammasomes Contributes to the Development of Proteinuria in Lupus Nephritis

Guo

Wang

et al. 2017

Arthritis & Rheumatology

159

107

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Objective Development of proteinuria in lupus nephritis (LN) is associated with podocyte dysfunction. The NLRP3 inflammasome has been implicated in the pathogenesis of LN. This study investigates whether NLRP3 inflammasome activation is involved in the development of podocyte injury in LN. Methods A fluorescence-labeled caspase-1 inhibitor probe was used to detect the activation of NLRP3 inflammasomes in podocytes in lupus-prone NZM2328 mice and in renal biopsies from LN patients. MCC950, a selective inhibitor of NLRP3, was used to treat NZM2328 mice. Proteinuria, ultrastructure of podocytes and renal pathology were evaluated. In vitro, sera from diseased NZM2328 mice were used to stimulate a podocyte cell line and cells were subjected to flow cytometry analysis. Results NLRP3 inflammasomes were activated in podocytes of lupus-prone mice and LN patients. Inhibition of NLRP3 with MCC950 ameliorated proteinuria, renal histological lesions and podocyte foot process effacement in lupus-prone mice. In vitro, sera from NZM2328 diseased mice activated NLRP3 inflammasomes in the podocyte cell line through reactive oxygen species (ROS) production. Conclusion NLRP3 inflammasomes were activated in podocytes of both LN patients and in lupus-prone mice. Activation of NLRP3 is involved in the pathogenesis of podocyte injuries and the development of proteinuria in LN.

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Mitochondrial dysfunction confers albumin-induced NLRP3 inflammasome activation and renal tubular injury

Abstract: . Mitochondrial dysfunction confers albumin-induced NLRP3 inflammasome activation and renal tubular injury.

Cited by 72 publications

References 23 publications

Inflammasomes in the Pathophysiology of Kidney Diseases

Inflammasomes in the Pathophysiology of Kidney Diseases

Mitochondria Targeted Peptide Attenuates Mitochondrial Dysfunction, Controls Inflammation and Protects Against Spinal Cord Injury-Induced Lung Injury

Podocyte Activation of NLRP3 Inflammasomes Contributes to the Development of Proteinuria in Lupus Nephritis

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