Homocysteine activates NADH/NADPH oxidase through ceramide-stimulated Rac GTPase activity in rat mesangial cells

Yi, Fan; Zhang, Andrew Y.; Janscha, Jennifer L.; Li, Pin‐Lan; Zou, Ai-Ping

doi:10.1111/j.1523-1755.2004.00968.x

Cited by 112 publications

(132 citation statements)

References 44 publications

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“…Yi and colleagues investigated this possibility and found that in a concentration-dependent fashion, homocysteine increased ceramide levels. At their highest dose of 80 μmol/L, they saw a 47% increase in ceramide levels [46]. Interestingly, they also found that increased levels of ceramide were independent of SMase.…”

Section: Homocysteine and Ceramidementioning

confidence: 93%

Ceramide: A common pathway for atherosclerosis?

et al. 2008

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Plasma sphingomyelin concentration is correlated with the development of atherosclerosis. It has been found to exist in significantly higher concentrations in aortic plaque. This appears to have clinical relevance as well as it has been shown to be an independent predictor of coronary artery disease. Ceramide, the backbone of sphingolipids, is the key component which affects atherosclerotic changes through its important second-messenger role. This paper sheds light on some of the current literature supporting the significance of ceramide with respect to its interactions with lipids, inflammatory cytokines, homocysteine and matrix metalloproteinases. Furthermore, the potential therapeutic implications of modulating ceramide concentrations are also discussed.

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Section: Homocysteine and Ceramidementioning

confidence: 93%

Ceramide: A common pathway for atherosclerosis?

et al. 2008

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“…Endostatin-mediated increase in intracellular ceramide levels in bovine coronary endothelial cells leads to enhanced superoxide production, suggesting a critical role of ceramide-mediated signaling in endostatin-induced endothelial dysfunction (Zhang et al, 2005). Recent studies with Fuminosin B1 and Myriocin in mesangial cells revealed that these inhibitors of the de novo synthesis pathway of ceramide prevent Lhomocysteine-induced ceramide formation and attenuate hyperhomocysteinemia-associated glomerular injury and proteinuria (Yi et al, 2004). Ceramide analogs and inhibitors of ceramide metabolism appear to be attractive targets for future therapy.…”

Section: Ceramide-based Therapeuticsmentioning

confidence: 99%

Recent advances in the immunobiology of ceramide

Pandey

Murphy

Agrawal

2007

Experimental and Molecular Pathology

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Ceramide, a sphingosine-based lipid molecule, has emerged as a key regulator of a wide spectrum of biological processes such as cellular differentiation, proliferation, apoptosis and senescence. Sphingomyelinase-dependent hydrolysis of sphingomyelin, and de novo synthesis involving the coordinated action of serinepalmitoyl transferase and ceramide synthase, are the two major pathways involved in ceramide synthesis. Clustering of plasma membrane rafts into ceramide enriched platforms serves as an important transmembrane signaling mechanism for cell surface receptors. Ceramides have been implicated in apoptosis, stress-signaling cascades as well as ion channels. There is accumulating evidence that targeted manipulation of ceramide metabolism pathway has immense therapeutic potential and may eventually prove to be a boon in the design of novel strategies and development of innovative treatments for diverse conditions including cardiovascular diseases, cancer and Alzheimer's disease. As yet uncharacterized natural ceramide analogs and novel inhibitors of ceramide metabolism might prove to be potent drugs. In this review, we discuss significant advances that continue to provide intriguing insights into the complex cellular and molecular mechanisms underlying ceramide-mediated signaling cascades.

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“…Of the proposed models of inflammasome activation, the ROS model provides an unifying link, utilizing the common aspect that all these danger signals produce changes in oxidative stress, making NALP3 a more general sensor detecting these changes in oxidative stress (23). Interestingly, we and others have found the damaging effects of hHcys to be strongly associated with increased local oxidative stress, majorly through NADPH oxidase (4,14,31). With reports of gp91 phox / Nox2 being the predominant isoform found in podocytes, our laboratory has also demonstrated that this NADPH oxidase isoform and its activity are essential for hHcys to induce glomerular injury, since knockout of the gp91 phox gene in mice protected podocytes and glomeruli from hHcys-induced glomerular sclerosis (35).…”

Section: Nadph Oxidase and Inflammasome Activation In Podocytesmentioning

confidence: 99%

“…Activation of the NALP3 inflammasome by increased ROS, the most widely accepted and considered to be the most plausible mechanism, suggests that this inflammasome is a general sensor for changes in cellular oxidative stress. ROS activation of inflammasomes within podocytes may be an early initiating mechanism of glomerular injury during hHcys, because the production of ROS has been considered to be one of the major early factors mediating hHcys-induced glomerular injury (24,31). In the kidney, there are many enzymatic systems that contribute to the production of ROS, including the mitochondria, xanthine/xanthine oxidase, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase.…”

Section: Introductionmentioning

confidence: 99%

NADPH Oxidase-Mediated Triggering of Inflammasome Activation in Mouse Podocytes and Glomeruli During Hyperhomocysteinemia

Abais

Zhang

Xia

et al. 2013

Antioxidants & Redox Signaling

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Aim: Our previous studies have shown that NOD-like receptor protein (NALP3) inflammasome activation is importantly involved in podocyte dysfunction and glomerular sclerosis induced by hyperhomocysteinemia (hHcys). The present study was designed to test whether nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-mediated redox signaling contributes to homocysteine (Hcys)-induced activation of NALP3 inflammasomes, an intracellular inflammatory machinery in podocytes in vitro and in vivo. Results: In vitro confocal microscopy and size-exclusion chromatography revealed that upon NADPH oxidase inhibition by gp91 phox siRNA, gp91ds-tat peptide, diphenyleneiodonium, or apocynin, aggregation of inflammasome proteins NALP3, apoptosis-associated speck-like protein (ASC), and caspase-1 was significantly attenuated in mouse podocytes. This NADPH oxidase inhibition also resulted in diminished Hcys-induced inflammasome activation, evidenced by reduced caspase-1 activity and interleukin-1b production. Similar findings were observed in vivo where gp91phox -/ -mice and mice receiving a gp91ds-tat treatment exhibited markedly reduced inflammasome formation and activation. Further, in vivo NADPH oxidase inhibition protected the glomeruli and podocytes from hHcys-induced injury as shown by attenuated proteinuria, albuminuria, and glomerular sclerotic changes. This might be attributed to the fact that gp91phox -/ -and gp91ds-tat-treated mice had abolished infiltration of macrophages and T-cells into the glomeruli during hHcys. Innovation: Our study for the first time links NADPH oxidase to the formation and activation of NALP3 inflammasomes in podocytes. Conclusion: Hcys-induced NADPH oxidase activation is importantly involved in the switching on of NALP3 inflammasomes within podocytes, which leads to the downstream recruitment of immune cells, ultimately resulting in glomerular injury and sclerosis. Antioxid. Redox Signal. 18, 1537-1548.

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Homocysteine activates NADH/NADPH oxidase through ceramide-stimulated Rac GTPase activity in rat mesangial cells

Abstract: These results indicate that Hcys activates NADH/NADPH oxidase by stimulating de novo ceramide synthesis, and subsequently enhancing Rac GTPase activity in rat MG cells. This ceramide-Rac GTPase signaling pathway may mediate Hcys-induced oxidative stress in these glomerular cells.

Cited by 112 publications

References 44 publications

Ceramide: A common pathway for atherosclerosis?

Ceramide: A common pathway for atherosclerosis?

Recent advances in the immunobiology of ceramide

NADPH Oxidase-Mediated Triggering of Inflammasome Activation in Mouse Podocytes and Glomeruli During Hyperhomocysteinemia

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