Protective Action of Anandamide and Its COX-2 Metabolite against L-Homocysteine-Induced NLRP3 Inflammasome Activation and Injury in Podocytes

Li, Guangbi; Xia, Min; Abais, Justine M.; Boini, Krishna M.; Li, Pin Lan; Ritter, Joseph K.

doi:10.1124/jpet.116.233239

Cited by 25 publications

(15 citation statements)

References 69 publications

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“…It has been well-characterized that Hcys-induced NLRP3 inflammasome activation results in the activation of caspase-1 and the proteolytic cleavage of IL-1 and IL-18 into their biologically active form, which produces other damageassociated molecular patterns (5,(57)(58)(59). Inflammatory cells, such as macrophages and T-cells, may be recruited in glomeruli by these factors released by podocytes, contributing to O 2…”

Section: Downloaded Frommentioning

confidence: 99%

NLRP3 inflammasome as a novel target for docosahexaenoic acid metabolites to abrogate glomerular injury

Chen

Bhat

et al. 2017

Journal of Lipid Research

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The nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome has been implicated in podocyte injury and glomerular sclerosis during hyperhomocysteinemia (hHcys). However, it remains unclear whether the NLRP3 inflammasome can be a therapeutic target for treatment of hHcys-induced kidney injury. Given that DHA metabolites-resolvins have potent anti-inflammatory effects, the present study tested whether the prototype, resolvin D1 (RvD1), and 17S-hydroxy DHA (17S-HDHA), an intermediate product, abrogate hHcys-induced podocyte injury by targeting the NLRP3 inflammasome. In vitro, confocal microscopy demonstrated that 17S-HDHA (100 nM) and RvD1 (60 nM) prevented Hcys-induced formation of NLRP3 inflammasomes, as shown by reduced colocalization of NLRP3 with apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) or caspase-1. Both DHA metabolites inhibited Hcys-induced caspase-1 activation and interleukin-1β production. However, DHA had no significant effect on these Hcys-induced changes in podocytes. In vivo, DHA lipoxygenase metabolites substantially inhibited podocyte NLRP3 inflammasome formation and activation and consequent glomerular sclerosis in mice with hHcys. Mechanistically, RvD1 and 17S-HDHA were shown to suppress Hcys-induced formation of lipid raft redox signaling platforms and subsequent O production in podocytes. It is concluded that inhibition of NLRP3 inflammasome activation is one of the important mechanisms mediating the beneficial action of RvD1 and 17S-HDHA on Hcys-induced podocyte injury and glomerular sclerosis.

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Section: Downloaded Frommentioning

confidence: 99%

NLRP3 inflammasome as a novel target for docosahexaenoic acid metabolites to abrogate glomerular injury

Chen

Bhat

et al. 2017

Journal of Lipid Research

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“…We speculate that MCC950 might reduce inflammation by blocking the positive feedback of COX-2 on NLRP3 inflammasomes. However, NLRP3 inflammasome activation is inhibited through its COX-2 metabolite, PGE2-EA, and this effect is inhibited by celecoxib [50]. At present, the relationship between NLRP3 inflammasomes and COX-2 is not clear in PD and needs further research in the future.…”

Section: Discussionmentioning

confidence: 96%

NLRP3 inflammasome inhibitor MCC950 attenuates primary dysmenorrhea in mice via the NF-κB/COX-2/PG pathway

et al. 2020

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Background: Primary dysmenorrhea (PD) constitutes a common gynecological disease among young women. The NLRP3 inflammasome may be activated and expressed in PD, but the mechanistic link between NLRP3 inflammasome activation and PD is still unclear. Methods: To investigate the potential role of NLRP3 inflammasome activation in the pathogenesis of PD, 30 female Kunming mice without pregnancy were used for experiments. The PD mouse model was constructed by 11 days of successive co-treatment with estradiol and oxytocin. MCC950, a potent and specific small-molecule inhibitor of the NLRP3 inflammasome, was used to treat PD mice. The disease level was assessed by the writhing response and hot water tail-flick test. The levels of prostaglandin E 2 (PGE 2) and prostaglandin F 2 alpha (PGF 2α) in the uterine tissues of mice were detected by ELISA. The expression levels of protein and cytokines, including NLRP3, cysteine aspartic acid-specific protease 1 (caspase-1), interleukin (IL)-1β, IL-18, nuclear factor kappa B (NF-κB) p65, phospho-NF-κB p65, and cyclooxygenase-2 (COX-2) were revealed by western blot analysis. Results: MCC950 greatly ameliorated the writhing response induced by the combination of oxytocin and estradiol, with an increasing length of tail-flick latency. MCC950 also significantly decreased the levels of PGF 2α and PGE 2 , and the expressions of NLRP3, caspase-1, IL-1β, IL-18, phospho-NF-κB p65, NF-κB p65, and COX-2 in the uterus. Conclusions: MCC950 markedly alleviated the pain and pathological damage in PD mice by inhibiting NLRP3 activation. The underlying mechanism may be related to hypoactive uterine inflammation via suppression of NLRP3 activation and the NF-κB/COX-2/PG pathway in uteruses of PD mice.

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“…AEA blocked Hcys-induced NLRP3 inflammasome activation in cultured podocytes and ameliorated podocyte dysfunction, ultimately precluding glomerular damage. 75 Therefore, while the former study demonstrated that an increase in CB 1 receptor gene expression accompanied by an upregulation in AEA and 2-AG is associated with podocyte injury, the latter study suggests that AEA exerts protective and anti-inflammatory effects in podocytes. Future studies are needed to investigate the role of EC ligands in CB receptor activation under varied conditions in renal health and disease.…”

Section: Ec System and Renal Diseasementioning

confidence: 95%

“…This is associated with signs of inflammation and podocyte injury, which manifest as decreased podocin and nephrin and increased desmin gene expression. 74 In contrast, Li et al 75 reported the protective functions of AEA following l -homocysteine (Hcys)-induced podocyte injury. AEA blocked Hcys-induced NLRP3 inflammasome activation in cultured podocytes and ameliorated podocyte dysfunction, ultimately precluding glomerular damage.…”

Section: Ec System and Renal Diseasementioning

confidence: 99%

Endocannabinoid System and the Kidneys: From Renal Physiology to Injury and Disease

Chua

Argueta

DiPatrizio

et al. 2019

Cannabis and Cannabinoid Research

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Introduction: As the prevalence of kidney disease continues to rise worldwide, there is accumulating evidence that kidney injury and dysfunction, whether acute or chronic, is associated with major adverse outcomes, including mortality. Meanwhile, effective therapeutic options in the treatment of acute kidney injury (AKI) and chronic kidney disease (CKD) have been sparse. Many of the effective treatments that are routinely utilized for different pathologies in patients without kidney disease have failed to demonstrate efficacy in those with renal dysfunction. Hence, there is an urgent need for discovery of novel pathways that can be targeted for innovative and effective clinical therapies in renal disease states. Discussion: There is now accumulating evidence that the endocannabinoid (EC) system plays a prominent role in normal renal homeostasis and function. In addition, numerous recent studies have described mechanisms through which alteration in the EC system can contribute to kidney damage and disease. These include a potential role for cannabinoid receptors in tubulo-glomerular damage and fibrosis, which are common features of AKI, interstitial nephritis, glomerulopathy, and other conditions leading to AKI and CKD. Conclusion: These findings suggest that manipulating the EC system may be an effective therapeutic strategy for the treatment of kidney disease and injury. However, further mechanistic studies are needed to fully delineate the role of this system in various conditions affecting the kidneys. Furthermore, while most of the current literature is focused on the role of the EC system as a whole in renal pathophysiology, future studies will also need to clarify the contribution of each component of this system, including the EC mediators, in the pathogenesis of kidney disease and their potential role as part of a therapeutic strategy.

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Protective Action of Anandamide and Its COX-2 Metabolite against L-Homocysteine-Induced NLRP3 Inflammasome Activation and Injury in Podocytes

Cited by 25 publications

References 69 publications

NLRP3 inflammasome as a novel target for docosahexaenoic acid metabolites to abrogate glomerular injury

NLRP3 inflammasome as a novel target for docosahexaenoic acid metabolites to abrogate glomerular injury

NLRP3 inflammasome inhibitor MCC950 attenuates primary dysmenorrhea in mice via the NF-κB/COX-2/PG pathway

Endocannabinoid System and the Kidneys: From Renal Physiology to Injury and Disease

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