A Rheostat of Ceramide and Sphingosine-1-Phosphate as a Determinant of Oxidative Stress-Mediated Kidney Injury
Abstract
:1. Introduction
2. SLs Metabolism
3. The Enzymes That Generate Ceramide and S1P in the Kidney
4. Interaction between ROS, Antioxidants and Ceramide in Oxidant-Induced Kidney Injury
4.1. Increased Ceramide Generation in Oxidant-Induced Kidney Injury
4.2. ROS Activate and Translocate the Enzymes That Generate Ceramide
4.3. Antioxidants Regulate the Enzymes That Generate Ceramide
4.4. Ceramide Stimulates ROS Production and Inhibits Antioxidant Defense System Which Further Activates Ceramide-Producing Enzymes
5. Role of Mitochondrial Function in the Regulation of Ceramide and ROS Formation
5.1. Interaction between Bcl-2 Family Proteins and the Enzymes That Generate Ceramide
5.2. Bcl-2 Family Proteins Regulate Ceramide-Induced ROS Production
6. Role of Mitochondria and Cell Signaling Pathways for Ceramide-Induced Apoptosis in Oxidant-Induced Kidney Injury
6.1. Ceramide-Induced Cell Death in Oxidant-Induced Kidney Injury
6.2. A Role of Mitochondria for the Regulation of ROS/Antioxidants and Ceramide Generation
6.3. Ceramide-Induced Mitochondrial Dysfunction Leading to Apoptosis
6.4. Ceramide-Induced Cell Signaling Pathway for Cell Death
7. Interaction between ROS and S1P in Oxidant-Induced Kidney Injury
7.1. Alteration of S1P Levels in Oxidative Stress-Mediated Kidney Disease
Oxidative Kidney Diseases | S1P Levels in Kidney and Plasma/Serum | Enzymes for S1P Alteration | Kidney Cell Response | References | |
---|---|---|---|---|---|
Toxic nephropathy Cadmium | kidney, plasma | kidney→, plasma↑ | kidney SphK1/2→, S1PR1→ | Necrosis/ Fibrosis | [208] |
Radiation | podocyte | ↓ | SMPDL3b↓ | Apoptosis | [35] |
Ischemia/reperfusion | RTC | ↓ | SphK1↓ | Necroptosis | [195] |
kidney | NA | SphK1↑, SphK2→, S1PR1/3↑ | Apoptosis/necrosis | [196] | |
EC | NA | SphK1↑, SphK2→ | Angiogenesis | [197] | |
Unilateral ureteral obstruction | Kidney, plasma | kidney; NA, plasma↑ | RTC; SphK1↑ | Autophagy/fibrosis | [201] |
Kidney | → | SphK→ | NA | [81] | |
Kidney | kidney; NA | SphK1↑, S1PR1-3 ↑ | Necrosis/fibrosis | [202] | |
Kidney, plasma | ↑ | SphK2↑ | Necrosis/fibrosis | [194] | |
Anti-GBM Ab GN | Spleen | NA | S1PR1/2/5 ↑ | Necrosis | [203] |
Nephrotic syndrome | Podocyte, serum | serum↑ | SGPL1↓ | FSGS | [83] |
Podocyte, fibroblast | fibroblast↓ | SGPL1↓ | FSGS | [84] | |
Chronic GN | Plasma | ↑ | UN | Necrosis | [209] |
Plasma | S1P↑, HDL-S1P↑ | UN | ESRD | [210] | |
Lupus nephritis | Plasma | ↓ | SGPL1↑ | NA | [93] |
Serum, urine | serum↑, urine→ | UN | NA | [211] | |
Kidney, serum | serum S1P↑, kidney, serum dhS1P↑ | SphK1/2↑ | Necrosis | [92,94] | |
Serum | serum S1P↑, dhS1P↑ | PBMC SphK2→ | NA | [212] | |
Diabetic nephropathy | Kidney | ↓ | UN | Apoptosis/MME/inflammation/ fibrosis | [43] |
Kidney, glomerulus, MC | ↑ | SphK↑ | Proliferation | [46,47] | |
MC | NA | SphK1↑ | Fibrosis | [198] | |
Kidney | ↑ | SphK1↑ | Necrosis/proliferation/ inflammation/fibrosis | [199] | |
Kidney, RTC | ↑ | SphK1↑ | Inflammation/fibrosis | [200] | |
Kidney, MC | NA | SphK1↑ | Fibrosis | [204] | |
VSMC | ↑ | SphK1↑, SphK2→ | Apoptosis | [205] | |
Plasma | ↑ | UN | Necrosis | [96,213] | |
Plasma | ↓ | UN | Necrosis | [214] |
7.2. ROS Regulate SphKs/S1P and Vice Versa and the Role of Mitochondria for Regulation of ROS by S1P
8. Roles of Mitochondria and Cell Signaling Pathways for S1P-Induced Cellular Function in Oxidant-Induced Kidney Injury
8.1. A Role of SphK1/2 for S1P-Induced Survival
8.2. Role of Mitochondria for S1P-Induced Cell Survival
8.3. Cell Signaling Pathways for S1P-Induced Cell Survival, Proliferation, Inflammation and Fibrosis
8.3.1. Apoptosis
8.3.2. Cell Proliferation
8.3.3. Inflammation
8.3.4. Renal Fibrosis
9. A Rheostat of Ceramide-S1P in the Regulation of Oxidative Stress-Mediated Kidney Injury
9.1. Balance between Ceramide and S1P Regulates Oxidant-Induced Kidney Injury
9.2. Targeting Enzymes for Ceramide Generation and SphKs That Improve Ceramide-S1P Rheostat, Contributing to Prevention against Oxidant-Induced Kidney Injury
10. Conclusions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
AIF | apoptosis-inducing factor |
AA | arachidonic acid |
aCDase | acid ceramidase |
AGEs | advanced glycation endproducts |
Ang II | angiotensin II |
apoM | apolipoprotein M |
AR | adenosine receptors |
aSMase | acid sphingomyelinase |
AdipoR | adiponectin receptor |
alCDase | alkaline CDase |
anti-GBM Ab GN | anti-glomerular basement membrane antibody-induced glomerulonephritis |
AMK | AMP-activated protein kinase |
BMMC | bone marrow-derived mononuclear cells |
BPGM | bisphosphoglycerate mutase |
CAMP | cyclic adenosine monophosphate |
CCl4 | carbon tetrachloride |
CDDO | methyl-2-cyano-3,12-dioxooleano-1,9-dien-28-oate |
Cer | ceramide |
CerK | Cer kinase |
CerS | Cer synthase |
CDase | ceramidase |
C1P | Cer-1-phosphate |
C1PP | C1P phosphatase |
C1PTP | C1P ransport protein |
CERT | ceramide transport protein |
CGN | chronic glomerulonephritis |
CKD | chronic kidney disease |
CK2α | casein kinase 2α |
COX-2 | cyclooxygenase-2 |
cPLA2 | cytosolic phospholipase A2 |
CREB | CAMP response element-binding protein |
CTGF | connective tissue growth factor |
Cyto C | cytochrome C |
DES | dihydroceramide desaturase |
dhCer | dihydroceramide |
dhSph | dihydrosphingosine |
DM | diabetes mellitus |
DN | diabetic nephropathy |
EA1P | ethanolamine 1-phosphate |
EC | endothelial cell |
ER | endoplasmic reticulum |
ERK | extracellular signal-regulated kinase |
eNOS | endothelial nitric oxide synthase |
FSGS | focal segmental glomerulosclerosis |
FPE | foot process effacement |
GCase | glycosidase |
GlcCer | glucosylceramide |
GCSs | glycosylceramide synthases |
GEC | glomerular EC |
GSLs | glycosphingolipids |
GPx | glutathione peroxidase |
GSSG | glutathione disulfide |
GSH | glutathione |
GST | glutathione s-transferase |
GTPase | guanosine triphosphatase |
HD | hexadecenal |
H2O2 | hydrogen peroxide |
HIF | hypoxia-inducible factor |
H/R | hypoxia/reoxygenation |
HO-1 | heme oxygenase-1 |
HREs | HIF-responsive-elements |
HSP | heat-shock protein |
ICAM-1 | intercellular adhesion molecule-1 |
IGF | insulin growth factor |
IGF-IIR | IGF-II receptor |
IGFBP-3 | IGF binding protein-3 |
iNOS | inducible nitric oxide synthase |
IL | interleukin |
I/R | ischemia/reperfusion |
JNK | Jun N-terminal protein kinase |
3-KdhSph | 3-ketodihydrosphingosine |
3-KR | 3-KdhSph reductase |
LIMK-1 | LIM kinase-1 |
LN | lupus nephritis |
LOX-1 | oxLDL receptor-1 |
LPS | lipopolysaccharide |
LRs | lipid rafts |
MAPK | mitogen-activated protein kinase |
MC | mesangial cell |
MAM | mitochondria-associated membrane |
MA-nSMase | mitochondria-associated nSMase |
MCLR | microcystin-LR |
MCP-1 | monocyte chemotactic protein-1 |
MEKK | mitogen-activated protein kinase kinase kinase |
MME | mesangial matrix expansion |
MMP | mitochondrial membrane potential |
MMP-9 | matrix metalloproteinase-9 |
MOMP | mitochondrial outer membrane permeability |
M6P | mannose 6-phosphate |
MPTP | mitochondrial transition pore |
MRCC | mitochondrial respiratory chain complex |
M6P/IGF-IIR | M6P/insulin-like growth factor II receptor |
NAC | N-acetylcysteine |
NADPH | nicotinamide adenine dinucleotide phosphate |
nCDase | neutral CDase |
Nfr-2 | nuclear factor-erythroid 2-related factor-2 |
NO | nitric oxide |
NOX | NADPH oxidase |
NF-κB | nuclear factor-κB |
nSMase | neutral SMase |
NS | nephrotic syndrome |
OxLDL | oxidized low-density lipoprotein |
PI3K | phosphatidylinositol3-kinase |
PDGF | platelet-derived growth factor |
PK | protein kinase |
PLA2 | phospholipase A2 |
PP2A | protein phosphatase 2A |
PHB2 | prohibitin 2 |
ROS | reactive oxygen species |
RTC | renal tubular cell |
SAPK | stress-activated protein kinase |
SGK-1 | serum- and glucocorticoid-inducible protein kinase-1 |
SLE | systemic lupus erythematosus |
SLs | sphingolipids |
SM | sphingomyelin |
SMPDL3b | sphingomyelin phosphodiesterase acid-like 3b |
SMS | SM synthase |
SOD | superoxide dismutase |
Sph | sphingosine |
SphKs | sphingosine kinases |
Spns2 | spinster homologue 2 |
S1P | sphingosine-1-phosphate |
S1PL | S1P lyase |
S1PP | S1P phosphatase |
S1PRs | S1P receptors |
SPT | serine palmitoyltransferase |
STAT | signal transducer and activator of transcription |
TIMP-1 | tissue inhibitor of matrix metalloproteinase-1 |
TNF | tumor necrosis factor |
TRAIL | TNF-related apoptosis inducing ligand |
UUO | unilateral ureteral obstruction |
UV | ultraviolet |
VDAC | voltage-dependent anion channel |
VEGF | vascular endothelial growth factor |
VSMC | vascular smooth muscle cell |
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Enzymes | Localization | References |
---|---|---|
SPT | kidney, podocyte, RTC, GEC | [14,15] |
DES | kidney, RTC | [16,17] |
SMS1/2 | kidney, RTC, EC | [18,19,20,21] |
aSMase | kidney, podocyte, glomerulus, MC, RTC, GEC, EC | [22,23,24,25,26,27,28,29,30,31] |
nSMase | kidney, MC, RTC, EC | [22,24,25,28,30,31,33,34] |
SMPDL3b | kidney, glomeruli, podocyte, GEC | [13,15,35] |
CerK | kidney, podocyte, MC, RTC, GEC | [13,15,36,37] |
CerS1 | RTC, EC | [38,39,40] |
CerS2 | kidney, RTC | [40,41] |
CerS4 | kidney, RTC | [40,41] |
CerS5 | kidney, RTC | [40,42] |
CerS6 | kidney, RTC | [40,41] |
aCDase | kidney, MC, podocyte, GEC | [24,35,43,44] |
nCDase | kidney, glomerulus, podocyte, MC, RTC | [24,25,35,45,46,47] |
alkaline CDase | MC, podocyte | [15,35,48] |
SphK1 | kidney, podocyte, MC, RTC, EC | [17,34,49,51,52,55] |
SphK2 | kidney, podocyte, MC, RTC, EC | [17,50,51,53,54,55] |
Oxidative Kidney Diseases | Cer Levels in Kidney, Plasma/Serum and Urine | Enzymes for Cer Production | Kidney Cell Response | References | |
---|---|---|---|---|---|
Toxic nephropathy | RTC | ↑ | CerS↑ | Apoptosis | [62] |
Cadmium | |||||
Carbon tetrachloride | Kidney, plasma | ↑ | nSMase↑, aSMase↓ | Apoptosis/necrosis | [31,63] |
Chromium | RTC | ↑ | SMPD2↑ | Autophagy | [64] |
Cisplatin | Kidney, BMK | ↑ | SPT↑, CerS↑, aSMae↑, GCS↑ | Apoptosis/necrosis | [65,66] |
Nickel | RTC | ↑ | CerS↑, GCS↑ | Apoptosis | [67] |
UV-irradiation | RTC, BMK | ↑ | SPT↑, aSMase↑, CerS↑ | Apoptosis | [27,65] |
Radiation | Podocyte | ↑ | SMPDL3b↓, nCDase↓, aCDase→, alkaline CDase→ | Apoptosis | [35] |
EC | ↑ | aSMase↑ | Apoptosis | [68,69,70] | |
GEC | ↑ | SMPDL3b↑, CerK→ | Apoptosis | [13] | |
Radiocontrasts | RTC | ↑ | CerS↑ | Apoptosis | [71] |
Oxalate nephrolithiasis | RTC | ↑ | SMase↑ | Apoptosis/necrosis | [72,73] |
Hypermocysteinemia | Kidney, glomerulus, Podocyte | ↑ | aSMase↑, SPT↑ | MME/necrosis/sclerosis/ fibrosis | [26,74,75] |
Myohemoglobinuria | Kidney, RTC | ↑ | aSMase↓ nSMase↓, CerS↑ | Necrosis | [22] |
Ischemia/reperfusion | Kidney, RTC | ↑ | aSMase↓, nSMase↓, CerS↑ | Apoptosis/necrosis | [22,76,77,78] |
EC | ↑ | SMase↑ | Necrosis | [79] | |
Unilateral ureteral obstruction | Kidney | NA | CerS↑ | Apoptosis | [71] |
Kidney | ↑ | UN | Apoptosis | [80,81] | |
Kidney | LCCer↓ | UN | Fibrosis | [82] | |
Anti-GBM Ab GN | Kidney | ↑ | aSMase↑, nSMase↑ | Necrosis | [22] |
Nephrotic syndrome | Glomerulus, podocyte | ↑ | aSMase↑, aCDase↓ | FPE | [44] |
Podocyte, fibroblast | ↑ | SGPL1↓, CerS2↑ | FPE, FSGS | [83] | |
Podocyte, serum | ↑ | SGPL1↓ | FPE, FSGS | [84] | |
Chronic GN | Plasma/serum | ↑ | UN | Necrosis | [90,91] |
Lupus nephritis | Plasma/serum | ↑ | UN | Necrosis | [92] |
Plasma | ↑ | CerS5↑ | Necrosis | [93] | |
Plasma | → | UN | Necrosis | [94] | |
Diabetic nephropathy | Kidney | ↑ | aCDase↓ | Apoptosis | [43] |
MC | → | nCDase↑,↓ | Proliferation | [47] | |
Kidney, RTC | ↑ | SPT↑, aSMase→ | Apoptosis | [85] | |
Podocyte | ↑ | SPT↑ | Apoptosis | [86] | |
Kidney | ↑ | UN | NA | [97] | |
Kidney | ↓ | CerS5↓, nSMase↓, alkaline CDase↑ | MME | [98] | |
EC | ↑ | aSMase↑, CerS↑ | Apoptosis/ necrosis | [87,88,89] | |
Plasma | ↑ | UN | NA | [96] | |
Plasma | ↑ | UN | MME/necrosis | [98,99] | |
Plasma | VLCer↓ | UN | Necrosis | [101] | |
Urine | ↑ | UN | Necrosis | [102,103] |
Targeted Enzyme | Effector (Function) | Model/Oxidant Stimuli | Tissue/Cell Type/Plasma | Effects | References |
---|---|---|---|---|---|
SPT | Myriosin (inhibitor) | Cisplatin nephropathy | kidney | Protects against apoptosis/necrosis | [66] |
hHcys | kidney | Protects against proteinuria and necrosis | [74] | ||
DN | kidney/podocyte | Prevents ROS production, albuminuria and apoptosis | [86] | ||
Coumesterol (inhibitor) | DM | hepatocyte | Improves insulin resistance | [296] | |
NAC * (inhibitor) | obesity/DM | plasma/cardiocyte | Improves insulin resistance | [297] | |
CerS | Fumonisin B1 (inhibitor) | Cadmium nephropathy | RTC | Prevents apoptosis | [62] |
Radiocontrast nephropathy | RTC | Prevents apoptosis | [71] | ||
H/R | RTC | Prevents apoptosis/necrosis | [76,78] | ||
CerS4,5 | Coumesterol (inhibitor) | DM | hepatocyte | Improves insulin resistance | [296] |
CerS5 | NAC * (inhibitor) | Obesity/DM | plasma/cardiocyte | Improves insulin resistance | [297] |
aSMase | Amitriptyline (inhibitor) | Cisplatin nephropathy | kidney | Prevents apoptosis/necrosis | [66] |
hHcys | podocyte | Protects against ROS production and necrosis | [75] | ||
Desipramin (inhibitor) | UV-irradiation nephropathy | RTC | Prevents apoptosis | [27] | |
alSMase, nSMase | NAC* (inhibitor) | Obesity/DM | plasma/cardiocyte | Improves insulin resistance | [297] |
aCDase | AdipoRon * (activator) | DN | kidney, podocyte, GEC | Increases S1P and protects against apoptosis | [43,284,298] |
nCDase | AdipoRon * (activator) | H2O2 | EC | Improves EC function | [281] |
Dexamethasone ** (activator) | Staurosporine, TNF-α | MC | Prevents apoptosis | [299] | |
SphK1 | SKI-II (inhibitor) | DN | RTC | Prevents inflammation and fibrosis | [200] |
Berberine (inhibitor) | DN | MC | Prevents fibrosis | [198] | |
kidney | Prevents injury | [264] | |||
Dimethylsphingosine (inhibitor) | DN | MC | Prevents fibrosis | [198] | |
Dimethylsphingosine (inhibitor) | LDL/DN | MC | Prevents fibrosis | [219] | |
Isoflurane (activator) | I/R | kidney | Prevents apoptosis | [285] | |
Coumesterol * (activator) | DM | hepatocyte | Improves insulin resistance | [296] | |
Dexamethasone (activator) | Staurosporine, TNF-α | MC | Prevents apoptosis | [299] | |
SphK2 | SLM6031434 (inhibitor) | UUO | renal fibroblast | Prevents fibrosis | [286] |
SLM6031434 (inhibitor) | DN | podocyte | Prevents podocyte function and fibrosis | [207] | |
HWG-35D (inhibitor) | UUO | renal fibroblast | Prevents fibrosis | [286] | |
SLP 120701 (inhibitor) | kidney | Prevents inflammation/fibrosis | [260] | ||
ABC294640 (inhibitor) | LN | glomeruli | Prevents injury | [94] | |
Coumesterol * (activator) | DM | hepatocyte | Improves insulin resistance | [296] | |
S1PR1 | FTY720 (activator) | Cisplatin nephropathy | kidney | Prevents injury | [226] |
FTY720 (activator) | I/R | kidney | Prevents injury | [287] | |
SEW2871 (activator) | |||||
Amiselimod (MT-1303) (activator) | LN | kidney | Prevents injury | [288] | |
Ozanimid (RPC-1063) (activator) | [289] | ||||
RP-101075 (activator) | [289] | ||||
KRP-203 (activator) | Prevents proteinuria and apoptosis | [290] | |||
S1PR2 | VPC23019 (inhibitor) | IgA GN | MC, RTC | Prevents cell proliferation and fibrosis | [291] |
JTE-013 (inhibitor) | DN | MC | Prevents fibrosis | [292] | |
GEC | Prevents ROS production and apoptosis | [293] | |||
Beberine (inhibitor) | kidney, MC | Prevents fibrosis | [264] | ||
S1PR1/3 | VPC23019 (inhibitor) | LDL/DN | MC | Prevents fibrosis | [219] |
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Ueda, N. A Rheostat of Ceramide and Sphingosine-1-Phosphate as a Determinant of Oxidative Stress-Mediated Kidney Injury. Int. J. Mol. Sci. 2022, 23, 4010. https://doi.org/10.3390/ijms23074010
Ueda N. A Rheostat of Ceramide and Sphingosine-1-Phosphate as a Determinant of Oxidative Stress-Mediated Kidney Injury. International Journal of Molecular Sciences. 2022; 23(7):4010. https://doi.org/10.3390/ijms23074010
Chicago/Turabian StyleUeda, Norishi. 2022. "A Rheostat of Ceramide and Sphingosine-1-Phosphate as a Determinant of Oxidative Stress-Mediated Kidney Injury" International Journal of Molecular Sciences 23, no. 7: 4010. https://doi.org/10.3390/ijms23074010