Role of Ceramide Synthase in Oxidant Injury to Renal Tubular Epithelial Cells

Ueda, Norishi; Camargo, Simone M. R.; Hong, Xiaoman; Basnakian, Alexei G.; Walker, Patrick D.; Shah, Sudhir V.

doi:10.1681/asn.v12112384

Cited by 32 publications

(8 citation statements)

References 34 publications

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“…12 The CERS inhibitor FB induces resistance to cell death and apoptosis after stress. 10,[13][14][15] We have shown previously that PDT-induced ceramide accumulation involves the de novo SL synthesis pathway and CERS. [16][17][18] This implies (a) that PDT induces ceramide generation in the ER, and (b) that PDT-induced apoptosis requires de novo SL synthesis and CERS.…”

Section: Introductionmentioning

confidence: 99%

Ceramide synthase inhibitor fumonisin B1 inhibits apoptotic cell death in SCC17B human head and neck squamous carcinoma cells after Pc4 photosensitization

Boppana

Kodiha

Stochaj

et al. 2014

Photochem Photobiol Sci

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The sphingolipid ceramide modulates stress-induced cell death and apoptosis. We have shown that ceramide generated via de novo sphingolipid biosynthesis is required to initiate apoptosis after photodynamic therapy (PDT). The objective of this study was to define the role of ceramide synthase (CERS) in PDT-induced cell death and apoptosis using fumonisin B1 (FB), a CERS inhibitor. We used the silicon phthalocyanine Pc4 for PDT, and SCC17B cells, as a clinically-relevant model of human head and neck squamous carcinoma. zVAD-fmk, a pan-caspase inhibitor, as well as FB, protected cells from death after PDT. In contrast, ABT199, an inhibitor of the anti-apoptotic protein Bcl2, enhanced cell killing after PDT. PDT-induced accumulation of ceramide in the endoplasmic reticulum and mitochondria was inhibited by FB. PDT-induced Bax translocation to the mitochondria and cytochrome c release were also inhibited by FB. These novel data suggest that PDT-induced cell death via apoptosis is CERS/ceramide-dependent.

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Section: Introductionmentioning

confidence: 99%

Ceramide synthase inhibitor fumonisin B1 inhibits apoptotic cell death in SCC17B human head and neck squamous carcinoma cells after Pc4 photosensitization

Boppana

Kodiha

Stochaj

et al. 2014

Photochem Photobiol Sci

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“…Ceramide contents and activity of enzymes involved in ceramide generation are altered in various types of oxidative stress-mediated kidney diseases ( Table 2 ) [ 13 , 22 , 26 , 27 , 31 , 35 , 43 , 44 , 47 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 ]. Ceramide levels were increased in the kidney tissue of toxic nephropathy [ 31 , 62 , 63 , 64 ...…”

Section: Interaction Between Ros Antioxidants and Ceramide In Oxidant...mentioning

confidence: 99%

“…In myohemoglobinuria and ischemia/reperfusion (I/R) kidney injury [ 22 ], levels of ceramide in the kidney were increased, likely due to CerS activation, since activity of aSMase and nSMase was reduced. Similarly, hypoxia/reoxygenation (H/R)-induced ROS activated CerS in RTCs [ 76 , 77 , 78 ] and SMase in ECs [ 79 ]. Ceramide levels were increased via the activation of aSMase in the kidney of anti-glomerular basement membrane (GBM) antibody (Ab)-induced glomerulonephritis (GN) [ 22 ] and unilateral ureteral obstruction (UUO) [ 80 , 81 ], although it was challenged [ 82 ].…”

Section: Interaction Between Ros Antioxidants and Ceramide In Oxidant...mentioning

confidence: 99%

“…Superoxide, hydrogen peroxide (H 2 O 2 ) and nitric oxide (NO) increased ceramide production in MCs [ 24 , 104 ] and GECs [ 104 ]. Hydrogen peroxide activated SMase [ 72 ] and CerS [ 77 ] in RTCs. Hydrogen peroxide directly phosphorylated the serine in position 173 of nSMase, leading to its activation in other types of cells [ 105 ].…”

Section: Interaction Between Ros Antioxidants and Ceramide In Oxidant...mentioning

confidence: 99%

“…Ceramide can induce apoptosis and/or necrosis in various types of kidney cells including ECs associated with oxidative stress-mediated kidney diseases ( Table 2 ) [ 13 , 22 , 26 , 27 , 31 , 35 , 43 , 62 , 63 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 97 , 98 , 99 , 100 , 101 , 102 , 103 ]. In support of this, exposure of MCs, GECs [ 104 ] and RTCs [ 77 ] to ROS [ 104 ] increased ceramide production, leading to apoptosis/necrosis, while antioxidants prevented ROS-induced ceramide production and apoptosis in ECs [ 70 ]. Thus, a crosstalk between ceramide and redox signaling contributes to the progression of oxidant-induced kidney injury.…”

Section: Role Of Mitochondria and Cell Signaling Pathways For Ceramid...mentioning

confidence: 99%

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

Ueda

2022

IJMS

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Reactive oxygen species (ROS) modulate sphingolipid metabolism, including enzymes that generate ceramide and sphingosine-1-phosphate (S1P), and a ROS-antioxidant rheostat determines the metabolism of ceramide-S1P. ROS induce ceramide production by activating ceramide-producing enzymes, leading to apoptosis, while they inhibit S1P production, which promotes survival by suppressing sphingosine kinases (SphKs). A ceramide-S1P rheostat regulates ROS-induced mitochondrial dysfunction, apoptotic/anti-apoptotic Bcl-2 family proteins and signaling pathways, leading to apoptosis, survival, cell proliferation, inflammation and fibrosis in the kidney. Ceramide inhibits the mitochondrial respiration chain and induces ceramide channel formation and the closure of voltage-dependent anion channels, leading to mitochondrial dysfunction, altered Bcl-2 family protein expression, ROS generation and disturbed calcium homeostasis. This activates ceramide-induced signaling pathways, leading to apoptosis. These events are mitigated by S1P/S1P receptors (S1PRs) that restore mitochondrial function and activate signaling pathways. SphK1 promotes survival and cell proliferation and inhibits inflammation, while SphK2 has the opposite effect. However, both SphK1 and SphK2 promote fibrosis. Thus, a ceramide-SphKs/S1P rheostat modulates oxidant-induced kidney injury by affecting mitochondrial function, ROS production, Bcl-2 family proteins, calcium homeostasis and their downstream signaling pathways. This review will summarize the current evidence for a role of interaction between ROS-antioxidants and ceramide-SphKs/S1P and of a ceramide-SphKs/S1P rheostat in the regulation of oxidative stress-mediated kidney diseases.

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Drug‐induced liver injury: Oltipraz and C2‐ceramide intervene HNF‐1α/GSTA1 expression via JNK signaling pathway

Zhang

Hao

et al. 2021

J of Applied Toxicology

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Drug‐induced liver injury (DILI) is a serious and frequently occurring issue in drug development. The c‐Jun N‐terminal kinase (JNK) signaling pathway plays an important role in many diseases; hepatocyte nuclear factor‐1α (HNF‐1α) and glutathione S‐transferase A1 (GSTA1) are important in regulating liver‐specific genes expressions and affecting drug metabolism. Oltipraz is used to treat liver cirrhosis by improving liver function, and C2‐ceramide is a pro‐apoptotic lipid that regulates multiple signaling pathways. In this study, we investigated the function of the JNK signaling pathway with HNF‐1α and GSTA1 in a cellular model of DILI and whether oltipraz and C2‐ceramide exert effects via the JNK pathway. The results showed that inhibiting JNK could ameliorate APAP‐induced hepatocyte injury, reduced oxidative stress, suppressed JNK and c‐Jun activation, and hepatocyte apoptosis. Meanwhile, the mRNA and protein expressions of HNF‐1α and GSTA1 were increased significantly compared to control conditions. The effect of oltipraz (8 μmol/L) was similar to a JNK inhibitor and significantly increased HNF‐1α/GSTA1 expression, but oltipraz combined with JNK inhibitor did not show a synergistic effect. Although C2‐ceramide (8 μmol/L) aggravated hepatocyte injury and apoptosis, exacerbated oxidative stress, increased phosphorylation of JNK and c‐Jun, and markedly decreased HNF‐1α/GSTA1 expression, C2‐ceramide combined with JNK inhibitor could partially alleviate these alterations. These results demonstrated that the JNK signaling pathway with HNF‐1α/GSTA1 are involved in the process of DILI. Inhibiting JNK up‐regulated HNF‐1α and GSTA1 expressions which could attenuate hepatocyte injury. Oltipraz and C2‐ceramide might affect the expression of HNF‐1α/GSTA1 though JNK signaling.

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Role of Ceramide Synthase in Oxidant Injury to Renal Tubular Epithelial Cells

Cited by 32 publications

References 34 publications

Ceramide synthase inhibitor fumonisin B1 inhibits apoptotic cell death in SCC17B human head and neck squamous carcinoma cells after Pc4 photosensitization

Ceramide synthase inhibitor fumonisin B1 inhibits apoptotic cell death in SCC17B human head and neck squamous carcinoma cells after Pc4 photosensitization

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

Drug‐induced liver injury: Oltipraz and C2‐ceramide intervene HNF‐1α/GSTA1 expression via JNK signaling pathway

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