A Rheostat of Ceramide and Sphingosine-1-Phosphate as a Determinant of Oxidative Stress-Mediated Kidney Injury

Ueda, Norishi

doi:10.3390/ijms23074010

Cited by 30 publications

(23 citation statements)

References 299 publications

(643 reference statements)

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“…ROS formation is considered the executioner of ferroptosis. Excessive ROS cause oxidative stress and exacerbate mitochondrial dysfunction, which lead to renal injury directly ( 47 ). The increased ROS level activates the inflammatory response to remote organ injury ( 48 ).…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic analysis and laboratory experiments reveal potential critical genes and regulatory mechanisms in sepsis-associated acute kidney injury

Liu¹,

Ao²,

Tan³

et al. 2022

Ann Transl Med

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Background Sepsis-associated acute kidney injury (SA-AKI) is one of the most frequent and serious complications of sepsis. However, the transcriptional regulatory network of the pathophysiological mechanism of the kidney has not been revealed. This study identified new mechanisms in SA-AKI using bioinformatics analyses and laboratory-based experiments. Methods We performed transcriptomic profiling of mouse kidneys after cecal ligation and puncture (CLP) to mimic clinical sepsis. RNA from kidney samples from the CLP and control groups was isolated and analyzed using bulk messenger RNA (mRNA)-seq. Differentially expressed genes (DEGs) between the two groups were identified, and GO, KEGG and GSEA pathway enrichment analyses were performed. The protein-protein interaction (PPI) network of DEGs and hub genes was analyzed. The hub genes were verified using quantitative real-time polymerase chain reaction (qPCR) or Western blotting. The interaction network, targeted microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) of hub genes were predicted, and the critical miRNA-hub gene regulatory axis was verified using qPCR, Western blotting, malondialdehyde (MDA) determination and flow cytometry. Correlation analyses of N6-adenosine methylation (m6A) RNA methylation regulators and hub genes and m6A modification analysis were performed. Results A total of 4,754 DEGs were identified between the two groups using high-throughput sequencing. The pathways in which DEGs were enriched included ferroptosis (the highest enrichment score), apoptosis, and the PI3K-Akt, NF-kappa B and IL-17 signaling pathways. Seven ( Hmox1, Spp1, Socs3, Mapk14, Lcn2, Cxcl1 and Cxcl12 ) of the 15 hub genes were involved in the KEGG pathway. mmu-miR-7212-5p-Hmox1 was a key RNA regulatory axis in ferroptosis. m6A RNA methylation modifications were involved in SA-AKI. The correlation analyses showed the close interactions among the m6A RNA methylation regulators and important hub genes. Conclusions The findings of this study provide new insights into the mechanism regulating the occurrence and progression of SA-AKI. The mmu-miR-7212-5p-Hmox1 axis in ferroptosis and m6A RNA methylation regulators may have potential clinical significance for the future treatment of SA-AKI. The datasets generated for this study can be found in the repository of the GEO database (Series number: GSE186822).

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Section: Discussionmentioning

confidence: 99%

Transcriptomic analysis and laboratory experiments reveal potential critical genes and regulatory mechanisms in sepsis-associated acute kidney injury

Liu¹,

Ao²,

Tan³

et al. 2022

Ann Transl Med

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“…It is well established that sphingolipid metabolism regulates pathologic inflammation underlying several disease states, and in particular, many studies have shown that SK activity regulates inflammation. 7,12,37 Sphingosine 1-phosphate induces NFκB, 38 which in turn can increase the proinflammatory enzymes nitric oxide synthase and cyclooxygenase-2 [39][40][41] generating prostaglandins and oxidative and nitrative stress mediated that exacerbate inflammation. 42 Inflammatory cytokines induce adhesion molecule expression via activation of SK and NFκB, and these proteins facilitate infiltration of neutrophils and macrophages into inflamed tissue.…”

Section: Discussionmentioning

confidence: 99%

“…[45][46][47] Overall, a strong body of evidence demonstrates that activation of SKs alters sphingolipid metabolism in favor of S1P formation, resulting in pro-inflammatory responses. More specific to the current studies, the roles of sphingolipids in IR injury to the kidneys have received attention, [10][11][12]48 largely because of their direct regulation of inflammation and ROS generation. 11,[49][50][51] Altered sphingolipid metabolism in response to renal ischemia was first demonstrated in 1997.…”

Section: Discussionmentioning

confidence: 99%

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The Sphingosine Kinase 2 Inhibitor Opaganib Protects Against Acute Kidney Injury in Mice

Maines¹,

Green²,

Keller³

et al. 2022

IJNRD

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Acute kidney injury (AKI) is a common multifactorial adverse effect of surgery, circulatory obstruction, sepsis or drug/ toxin exposure that often results in morbidity and mortality. Sphingolipid metabolism is a critical regulator of cell survival and pathologic inflammation processes involved in AKI. Opaganib (also known as ABC294640) is a first-in-class experimental drug targeting sphingolipid metabolism that reduces the production and activity of inflammatory cytokines and, therefore, may be effective to prevent and treat AKI. Methods: Murine models of AKI were used to assess the in vivo efficacy of opaganib including ischemia-reperfusion (IR) injury induced by either transient bilateral occlusion of renal blood flow (a moderate model) or nephrectomy followed immediately by occlusion of the contralateral kidney (a severe model) and lipopolysaccharide (LPS)-induced sepsis. Biochemical and histologic assays were used to quantify the effects of oral opaganib treatment on renal damage in these models. Results: Opaganib suppressed the elevations of creatinine and blood urea nitrogen (BUN), as well as granulocyte infiltration into the kidneys, of mice that experienced moderate IR from transient bilateral ligation. Opaganib also markedly decreased these parameters and completely prevented mortality in the severe renal IR model. Additionally, opaganib blunted the elevations of BUN, creatinine and inflammatory cytokines following exposure to LPS. Conclusion:The data support the hypotheses that sphingolipid metabolism is a key mediator of renal inflammatory damage following IR injury and sepsis, and that this can be suppressed by opaganib. Because opaganib has already undergone clinical testing in other diseases , the present studies support conducting clinical trials with this drug with surgical or septic patients at risk for AKI.

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“…It has been shown that ROS play an important role in ceramide-mediated apoptosis. On the other hand, ROS induce the production of ceramides by activating ceramide-producing enzymes, which leads to apoptosis, while inhibiting the production of S1P, which promotes survival [84,85].…”

Section: Sphingolipids Implication In the Pathogenesis Of Abdominal A...mentioning

confidence: 99%

The Role of Obesity, Inflammation and Sphingolipids in the Development of an Abdominal Aortic Aneurysm

2022

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Abdominal aortic aneurysm (AAA) is a local dilatation of the vessel equal to or exceeding 3 cm. It is a disease with a long preclinical period commonly without any symptoms in its initial stage. Undiagnosed for years, aneurysm often leads to death due to vessel rupture. The basis of AAA pathogenesis is inflammation, which is often associated with the excess of adipose tissue, especially perivascular adipose tissue, which synthesizes adipocytokines that exert a significant influence on the formation of aneurysms. Pro-inflammatory cytokines such as resistin, leptin, and TNFα have been shown to induce changes leading to the formation of aneurysms, while adiponectin is the only known compound that is secreted by adipose tissue and limits the development of aneurysms. However, in obesity, adiponectin levels decline. Moreover, inflammation is associated with an increase in the amount of macrophages infiltrating adipose tissue, which are the source of matrix metalloproteinases (MMP) involved in the degradation of the extracellular matrix, which are an important factor in the formation of aneurysms. In addition, an excess of body fat is associated with altered sphingolipid metabolism. It has been shown that among sphingolipids, there are compounds that play an opposite role in the cell: ceramide is a pro-apoptotic compound that mediates the development of inflammation, while sphingosine-1-phosphate exerts pro-proliferative and anti-inflammatory effects. It has been shown that the increase in the level of ceramide is associated with a decrease in the concentration of adiponectin, an increase in the concentration of TNFα, MMP-9 and reactive oxygen species (which contribute to the apoptosis of vascular smooth muscle cell). The available data indicate a potential relationship between obesity, inflammation and disturbed sphingolipid metabolism with the formation of aneurysms; therefore, the aim of this study was to systematize the current knowledge on the role of these factors in the pathogenesis of abdominal aortic aneurysm.

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A Rheostat of Ceramide and Sphingosine-1-Phosphate as a Determinant of Oxidative Stress-Mediated Kidney Injury

Cited by 30 publications

References 299 publications

Transcriptomic analysis and laboratory experiments reveal potential critical genes and regulatory mechanisms in sepsis-associated acute kidney injury

Transcriptomic analysis and laboratory experiments reveal potential critical genes and regulatory mechanisms in sepsis-associated acute kidney injury

The Sphingosine Kinase 2 Inhibitor Opaganib Protects Against Acute Kidney Injury in Mice

The Role of Obesity, Inflammation and Sphingolipids in the Development of an Abdominal Aortic Aneurysm

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