The key role of NLRP3 and STING in APOL1-associated podocytopathy

Wu, Junnan; Raman, Archana; Coffey, Nathan J.; Sheng, Xin; Wahba, Joseph; Seasock, Matthew J.; Ma, Ziyuan; Beckerman, Pazit; Laczkó, Dorottya; Palmer, Matthew; Kopp, Jeffrey B.; Kuo, Jay J.; Pullen, Steven S.; Boustany-Kari, Carine M.; Linkermann, Andreas; Suszták, Katalin

doi:10.1172/jci136329

Cited by 90 publications

(74 citation statements)

References 63 publications

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“…Dose-dependent APOL1 cytotoxicity was also reported in similar cell-based systems (34). Moreover, APOL1 transgenic mouse models have not only validated the causal link between APOL1 risk alleles and podocyte injury but have demonstrated that the degree of podocytopathy correlated with APOL1 expression levels (10,(12)(13)(14)35). Our discovery that 8 of 9 patients with COVAN demonstrated robust glomerular APOL1 expression relative to control individuals and the evidence that expression of endogenous APOL1 risk alleles causes podocytopathy in human kidney micro-organoids support the causal link between APOL1 and podocytopathy.…”

Section: Discussionmentioning

confidence: 61%

“…This hypothesis was supported by recent reports that transgenic overexpression of APOL1 risk alleles in mouse podocytes or GECs caused podocytopathy, endotheliopathy, glomerulopathy, and clinical manifestations of kidney failure (10)(11)(12)(13)(14). These murine disease models suggest that the mechanism that underlies COVID-19-induced APOL1 expression would be a potential therapeutic target for COVAN.…”

Section: Introductionmentioning

confidence: 54%

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JAK inhibitor blocks COVID-19 cytokine–induced JAK/STAT/APOL1 signaling in glomerular cells and podocytopathy in human kidney organoids

Nystrom

Datta

et al. 2022

JCI Insight

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Section: Discussionmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 54%

JAK inhibitor blocks COVID-19 cytokine–induced JAK/STAT/APOL1 signaling in glomerular cells and podocytopathy in human kidney organoids

Nystrom

Datta

et al. 2022

JCI Insight

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“…Both inhibiting cGAS and STING promoted recovery from acute kidney injury induced by cisplatin [ 43 ]. Novel data suggest that inhibiting the cGAS/STING pathway might also be beneficial in treating ApoL1 nephropathy [ 44 ].…”

Section: The Cgas/sting a Nucleic Acid Sensing Pathway Plays A Role I...mentioning

confidence: 99%

STING Agonists/Antagonists: Their Potential as Therapeutics and Future Developments

Guerini

2022

Cells

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The cGAS STING pathway has received much attention in recent years, and it has been recognized as an important component of the innate immune response. Since the discovery of STING and that of cGAS, many observations based on preclinical models suggest that the faulty regulation of this pathway is involved in many type I IFN autoinflammatory disorders. Evidence has been accumulating that cGAS/STING might play an important role in pathologies beyond classical immune diseases, as in, for example, cardiac failure. Human genetic mutations that result in the activation of STING or that affect the activity of cGAS have been demonstrated as the drivers of rare interferonopathies affecting young children and young adults. Nevertheless, no data is available in the clinics demonstrating the therapeutic benefit in modulating the cGAS/STING pathway. This is due to the lack of STING/cGAS-specific low molecular weight modulators that would be qualified for clinical exploration. The early hopes to learn from STING agonists, which have reached the clinics in recent years for selected oncology indications, have not yet materialized since the initial trials are progressing very slowly. In addition, transforming STING agonists into potent selective antagonists has turned out to be more challenging than expected. Nevertheless, there has been progress in identifying novel low molecular weight compounds, in some cases with unexpected mode of action, that might soon move to clinical trials. This study gives an overview of some of the potential indications that might profit from modulation of the cGAS/STING pathway and a short overview of the efforts in identifying STING modulators (agonists and antagonists) suitable for clinical research and describing their potential as a “drug”.

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“…The inflammasome acts by activating the effector molecule pro–caspase-1 to form active caspase-1. Activated caspase-1 is able to specifically cleave the GSDMD to generate the N-terminal and C-terminal ends, and the N-terminal end of the GSDMD binds to cell membrane phospholipids, causing many small pores to form in the cell membrane ( 102 , 103 ). The integrity of the cell is disrupted, and the water flows inward, leading to cell swelling and rupture, releasing intracellular inflammatory substances, and inducing pyroptosis ( 104 ).…”

Section: Pyroptosismentioning

confidence: 99%

Ferroptosis, necroptosis, and pyroptosis in the occurrence and development of ovarian cancer

Zhang

Liu

2022

Front. Immunol.

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Ovarian cancer (OC) is one of the most common malignancies that causes death in women and is a heterogeneous disease with complex molecular and genetic changes. Because of the relatively high recurrence rate of OC, it is crucial to understand the associated mechanisms of drug resistance and to discover potential target for rational targeted therapy. Cell death is a genetically determined process. Active and orderly cell death is prevalent during the development of living organisms and plays a critical role in regulating life homeostasis. Ferroptosis, a novel type of cell death discovered in recent years, is distinct from apoptosis and necrosis and is mainly caused by the imbalance between the production and degradation of intracellular lipid reactive oxygen species triggered by increased iron content. Necroptosis is a regulated non-cysteine protease–dependent programmed cell necrosis, morphologically exhibiting the same features as necrosis and occurring via a unique mechanism of programmed cell death different from the apoptotic signaling pathway. Pyroptosis is a form of programmed cell death that is characterized by the formation of membrane pores and subsequent cell lysis as well as release of pro-inflammatory cell contents mediated by the abscisin family. Studies have shown that ferroptosis, necroptosis, and pyroptosis are involved in the development and progression of a variety of diseases, including tumors. In this review, we summarized the recent advances in ferroptosis, necroptosis, and pyroptosis in the occurrence, development, and therapeutic potential of OC.

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The key role of NLRP3 and STING in APOL1-associated podocytopathy

Cited by 90 publications

References 63 publications

JAK inhibitor blocks COVID-19 cytokine–induced JAK/STAT/APOL1 signaling in glomerular cells and podocytopathy in human kidney organoids

JAK inhibitor blocks COVID-19 cytokine–induced JAK/STAT/APOL1 signaling in glomerular cells and podocytopathy in human kidney organoids

STING Agonists/Antagonists: Their Potential as Therapeutics and Future Developments

Ferroptosis, necroptosis, and pyroptosis in the occurrence and development of ovarian cancer

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