Ochratoxin A-Induced Nephrotoxicity: Up-to-Date Evidence
Abstract
:1. Introduction
2. The Mechanisms Underlying OTA Nephrotoxicity
2.1. Oxidative Stress
2.2. Nitrosative Stress
2.3. Apoptosis/Pyroptosis
2.4. DNA Damage/Genotoxicity
2.5. Epigenetic Modification
2.6. Inhibition of Protein Synthesis
2.7. Cell Cycle Arrest
2.8. Lipotoxicity
2.9. Mitochondrial Dysfunction/ATP
2.10. miRNA
2.11. Autophagy
2.12. EMT/Fibrosis/Tight Junction
2.13. Other Mechanisms
3. Prevention
3.1. Antioxidant
3.1.1. Ursolic Acid (UA)
3.1.2. Hydroxytyrosol
3.1.3. N-Acetyl-L-tryptophan (NAT)
3.1.4. Troxerutin
3.1.5. Taurine
3.1.6. δ-Tocotrienol (Delta)
3.1.7. Curcumin
3.1.8. Yemeni Green Coffee/Red Orange and Lemon Extract (RLE)
3.1.9. Recombinant Mitochondrial Manganese Containing Superoxide Dismutase (rMnSOD)
3.1.10. Astaxanthin (ASX)
3.2. Nrf2 Activator
3.2.1. Luteolin (LUT)
3.2.2. Sulforaphane (SFN)
3.3. Trace Element
3.3.1. Selenium
3.3.2. Zinc
3.4. Nanoparticle
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
8-OHdG | 8-Hydroxy-2′-Deoxy Guanosine |
Aco2 | aconitase 2 |
AMPK | AMP-activated protein kinase |
AhR | aryl hydrocarbon receptor |
Akt | serine/threonine-specific protein kinases |
ATP | adenosine triphosphate |
α-SMA | alpha-smooth muscle actin |
Bax | Bcl-2 associated x protein |
β-catenin | beta-catenin |
CAT | catalase |
Cdk2 | cyclin dependent kinase 2 |
Cdk4 | cyclin dependent kinase 4 |
CHOP | CAAT/enhancer-binding protein (C/EBP) homologous protein |
c-MET | tyrosine protein kinase MET |
CREB | cyclin-AMP responsive-element binding protein |
CYP1A1 | cytochrome P450 1A1 |
CYP1A2 | cytochrome P450 1A2 |
CYP3A4 | cytochrome P450 3A4 |
CypD | cyclophilin D |
CytC | cytochrome C |
DNMT1 | DNA methyltransferase 1 |
DNMT3b | DNA methyltransferase 3b |
DUSP3 | dual specificity phosphatase 3 |
DUSP4 | dual specificity phosphatase 4 |
EMT | epithelial-to-mesenchymal transition |
EPO | erythropoietin |
ER stress | endoplasmic reticulum stress |
ERK | extracellular signal-regulated kinases |
ERK 1/2 | extracellular signal-regulated kinases 1/2 |
ESRD | end stage renal disease |
GCLC | glutamate-cysteine ligase catalytic subunit |
GFR | glomerular filtration rate |
GPx | glutathione peroxidase |
GPx1 | glutathione peroxidase 1 |
GRP75 | glucose-regulated protein 75 |
GRP78 | glucose-regulated protein 78 |
GSH | glutathione |
GST | glutathione S-transferase |
H3K9 | histone 3 lysine 9 |
HDAC1 | histone deacetylase 1 |
HIF-1α | hypoxia inducible factor-1 alpha |
HO-1 | heme oxygenase-1 |
HSP75 | heat shock protein 75 |
IL-1B | interleukin 1 beta |
IL-6 | interleukin 6 |
iNOS | inducible nitric oxide synthase |
JAK2 | Janus kinase 2 |
Keap1 | kelch-like ECH-associated protein 1 |
LDH | lactate dehydrogenase |
Lonp1 | lon protease 1 |
MAPK | mitogen-activated protein kinase |
MDA | malondialdehyde |
MEK 1/2 | mitogen-activated protein kinase kinase 1/2 |
mTOR | mammalian target of rapamycin |
NF-κB | nuclear factor kappa-light-chain-enhancer of activated B cell |
NHE3 | sodium-hydrogen exchanger isoform 3 |
NLRP3 | NOD-like receptor protein 3 |
NO | nitric oxide |
Notch | neurogenic locus notch homolog protein |
NQO1 | NADPH quinone oxidoreductase 1 |
Nrf2 | nuclear factor erythroid 2-related factor 2 |
OAT | organic anion transporter |
OCT2 | organic cation transporters 2 |
OTα | ochratoxin alpha |
P450 | cytochrome p450 |
PARP | poly(ADP-ribose) polymerase |
PDK1 | pyruvate dehydrogenase kinase 1 |
PHLPP | Ph domain and leucine-rich repeat protein phosphatase |
PI3K | phosphoinositide 3-kinases |
PPAR-α | peroxisome proliferator-activated receptor alpha |
pRB | retinoblastoma protein |
PTEN | phosphatase and tensin homolog |
PUMA | p53 upregulated modulator of apoptosis |
PXR | pregnane X receptor |
rMNSOD | recombinant mitochondrial manganese-containing superoxide dismutase |
Ras | rat sarcoma virus |
ROS | reactive oxygen species |
Smad2/3 | small mothers against decapentaplegic 2/3 |
SMase | sphingomyelinase |
SOCS3 | suppressors of cytokine signaling3 |
SOD | superoxide dismutase |
STAT3 | signal transducer and activator of transcription 3 |
TG | triacylglycerol |
TGF-β | transforming growth factor beta |
TNF-α | tumor necrosis factor alpha |
tRNA | transfer RNA |
TRAP-1 | tumor necrosis factor receptor-associated protein 1 |
UPS | ubiquitin-proteasome system |
VEGF | vascular endothelial growth factor |
ZO-1 | Zonula occludens protein 1 |
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Cell Type | Time | Dose | Result/Conclusion | Reference |
---|---|---|---|---|
HK-2 | 24 h | 2–8 uM | OTA induced HK-2 apoptosis by regulating PTEN/Akt signaling pathway through impaired lipid raft formation | Song et al. [40] |
HK-2 | 48 h | 200 nM | OTA induced nephrotixicity through AhR Smad2/3 HIF-1α signaling pathway | Pyo et al. [41] |
HK-2 | 24 h | 0.2, 1, 5 uM | Oleanolic acid (OA) promoted TRAP-1 to relieve mitochondrial mediated and ER stress excited apoptosis | Zhang et al. [42] |
HK-2 | 1, 3, 6, 12, 24 h | 10 uM | OTA activated NF-kB to induce ERK 1/2-dependent apoptosis | Darbuka et al. [43] |
PTEC | 24, 72 h | 0–100 uM | OTA downregulated transciptional expression of GST leading to nephrotoxicity; organic anionic membrane transporter(s) are involved in the excretion of OTA | Imoaka et al. [89] |
HKC | 24 h | 20 uM | OTA cause G0/G1 phase arrest; OTA altered methylation state of specific gene which regulated cell cycle | Zhang et al. [58] |
HK-2 | 24 h | 10, 25 uM | OTA suppressed cyclin D1, CDk2, and CDk4 through p53 | Asci et al. [65] |
HEK 293 | 24 and 48 h | 0.125–0.5 uM | OTA promoted expression of PDK1, HIF-1α, TGF-β, VEGF and EPO; OTA increased ATP production | Raghubeer et al. [87] |
HK-2, MEF | 1–24 h | 10 uM | OTA induced autophagy and UPS to activate PI3K/AKT and MAPK/ERK1–2 signaling pathway | Akpinar et al. [77] |
PK 15, PAM | 24 h | 2–8 ug/mL | OTA induced cytotoxicity, apoptosis, DNA damage through DNMT1-JAK2/STAT3 -SOCS3 signaling pathway | Gan et al. [53] |
PK 15 | 48 h | 2–8 uM | Protective autophagy induced by OTA through inhibition of ATK/mTOR signaling pathway | Qian et al. [78] |
MDCK | 24 h | 0–1.2 ug/mL | OTA reduced occludin and ZO-1; alpha-tocopherol maintain occludin, ZO-1 | Fusi et al. [81] |
HK-2 | 24 h | 0–50 uM | OTA induced H3K9 hypoacetylation, leading to suppressed gene expression | Limbeck et al. [57] |
HKC, NRK-52E | 72 h | 1–2 uM | OTA induced senescence by activating p53-p21 and p16-pRB signaling pathway | Yang et al. [84] |
PK 15, porcine primary splenocyte | 24 h | 0.5–8 ug/mL | OTA induced nephrotoxicity through p38 pathway, OTA induced immunotoxicity through ERK pathway | Gan et al. [44] |
HK-2, HEK293T | 24 h | 10, 100 nM | OTA downregulated CDK2 leading to G1 phase cell cycle arrest | Dubourg et al. [66] |
Animal Model | Cell Type | Time | Dose | Result | Reference |
---|---|---|---|---|---|
C57BL/6 mice OTA: 1.0, 2.0 mg/kg IP; 14 days | MDCK | 24 h | 0–4 uM | OTA activated NLRP3 inflammasome and caspase-1 dependent pyroptosis | Li et al. [46] |
C57BL/6 mice OTA 0.5, 1.5, 2.5 mg/kg IP; 3 weeks | HMC | 48 h | 0–8 uM | OTA induced glomerular injury by ERK/NF-kB pathway in vivo and in vitro | Le et al. [80] |
ICR mice OTA: 200, 1000 ug/kg; 12 weeks | HK-2 | 48 h | 50–200 nM | OTA induced EMT and renal fibrosis by TGF-β/Smad2/3 and B-catenin/Wnt signaling pathway in vivo and in vitro | Pyo et al. [79] |
Piglet OTA: 50, 200 ug/kg; 28 days | OTA upregulated expression of miR-497, miR-133a-3p, miR-423-3p, miR-34a, miR-542-3p and downregulated expression of miR-421-3p, miR-490, and miR-9840-3p | Marin et al. [74] | |||
SPF F344, Wistar rat OTA: 0, 70, 210 ug/kg; 13 weeks | HKC | 48 h | 0–25 uM | OTA induced GRP75 to prevent renal injury and mitochondrial dysfunction | Yang et al. [73] |
ICR mice OTA: 1–3 ug/kg; 6 weeks | HK-2 | 48 h | 25–200 nM | OTA induced ROS production through AhR, PXR and Nrf2 signaling pathway | Lee et al. [31] |
Rats OTA: 70, 210 ug/kg; 4 weeks, 13 weeks | NRK-52E | 24 h | 20, 50 uM | OTC2 modulated OTA-induced apoptosis | Qi et al. [45] |
HO-1 knock out mice OTA: 2.5 mg/kg; IP; 20 days | LLC-PK1 | 20–60 min, 24 h | 25 uM | HO-1 mitigated OTA nephrotoxicity thorough regulating Nrf-2, miR-34a, and miR-21 | Loboda et al. [86] |
Nrf-2 knock out mice OTA: 2.5 mg/kg; IP; 20 days | LLC-PK1 | 24 h | 25 uM | OTA induced nephrotixcity is sex-dependent: increased renal injury in male Nrf-2 knockout mice | Loboda et al. [88] |
Protective Agent | Animal Model | Cell Type | OTA Dose | Result/Conclusion | Reference |
---|---|---|---|---|---|
Oleanolic acid (OA) | HK-2 | 0.2, 1, 5 uM | OA promoted TRAP-1 to relieve mitochondrial mediated and ER stress excited apoptosis | Zhang et al. [42] | |
Curcumin (CURC) | SD rats; OTA 0.5 mg/kg; 14 days | Curcumins attenuated OTA-induced nitosative stress, inflammatory, and DNA damage in kidney and liver of rats | Longobardi et al. [34] | ||
Taurine | PK 15 | 1–6 uM | Taurine reversed apoptosis, increasing LDH level induced by OTA | Liu et al. [92] | |
Luteolin (LUT) | NRK-52E | 50 uM | LUT alleviated ROS production, loss of mitochondrial membrane potential induced by OTA; LUT enhanced expression of Nrf2 and HIF-1α | Liu et al. [114] | |
N-Acetyl-L-Tryptophan (NAT) | HEK 293T | 4 ug/mL | NAT ameliorated OTA-induced cell cycle arrest, mitochondrial membrane potential disturbance, protein inhibition | Argawa et al. [61] | |
Astaxanthin(ASX) | C57BL/J mice OTA 5 mg/kg; 27 days | ASX ameliorated apoptosis, oxidative stress induced by OTA; ASX activate Nrf2/Keap1 signaling pathway | Li et al. [100] | ||
Curcumin (CURC) | SD rat OTA 0.5 mg/kg: 14 days | Curcumins maintained GFR, attenuated oxidative stress, glomerular, and tubular damage, tubular interstitial fibrosis | Damino et al. [95] | ||
Hydroxytyrosol (HT) | SD rat OTA 250 ug/kg: 90 days | MDCK, LLC-PK1, RK 13 | 2.5 ug/mL | HT decreased ROS production, enhanced cell viability; HT decreased renal fibrosis, oxidative stress in vitro after OTA exposure. | Crupi et al. [33] |
Selenium Yeast (Se-Y) | chicken OTA 50 ug/kg, 80 days | Se-Y against OTA induced apoptosis, oxidative stress, renal injury in chicken | Li et al. [115] | ||
Copper nanoparticles and aluminum silicate nanoparticles | Nile tilapia fish OTA 1 mg/kg; 6 weeks | Nanoparticle aluminum silicate or copper ameliorated OTA-induced liver and kidney injury | Fadl et al. [111] | ||
Selenium | PK 15 | 4 ug/mL | Selenium promoted GPx1 expression to decrease DNMT1, DNA damage after OTA exposure. | Gan et al. [103] | |
Yemeni green coffee powder | Wistar rats OTA 10 mg/kg; 28 days | Yemeni green coffee restored SOD, glutathione level; it reduced kidney injury after OTA exposure | Nogaim et al. [96] | ||
Red orange and lemon extract (RLE) | SD rats OTA 0.5 mg/kg/day; 14 days | RLE reversed GSH level and GFR; it reduced oxidative stress, renal fibrosis, glomerual damage and tubular damage | Damino et al. [97] | ||
Ursolic acid (UA) | HEK 293T | 8 uM | UA decreased ROS production, enhanced cell viability, reversed inhibition of LonP1 by OTA | Li et al. [90] | |
Troxerutin | Specific-pathogen–free male CD1 (ICR) mice OTA 1 mg/kg; 4 weeks, 12 weeks | Troxerutin alleviated OTA-induced lipid accumulation, lipid peroxidation, increased TG and SMase level | Yang et al. [67] | ||
Zinc supplement | MDCK | 1.0 ug/mL | Zinc supplement suppressed ROS production and apoptosis through enhanced metallothionein | Li et al. [108] | |
δ-tocotrienol (Delta) | male, SD rats OTA, 0.5 mg/kg, gavage, 14 days | δ-tocotrienol alleviated ROS production induced by OTA | Damino et al. [93] | ||
rMnSOD | male, SD rats OTA, 0.5mg/kg, gavage, 14 days | rMnSOD restored suppression of fluid reabsorption, decreased NHE3 and NO production by OTA | Damino et al. [35] | ||
Sulforaphane (SFN) | Nrf-2 knock out mice: 2.5 mg/kg; IP; 20 days | LLC-PK1 | 25 uM | SFN alleviated OTA-induced inflammatory cytokine and apoptotic factor | Laboda et al. [88] |
Selenoprotein S (SelS) | PK 15 | 1–4 ug/mL | SelS alleviated OTA-induced apoptosis and ROS production | Gan et al. [105] | |
Selenium probiotics (SP) | Piglet, OTA 0.4 mg/kg; 6 weeks | SP restored GPx, SOD against OTA-induced kidney injury | Gan et al. [106] | ||
Chitosan nanoparticles (COS) plus quercetin (Q) | SD rats 3 mg/kg; diet; 3 weeks | COS alone or plus Q mitigated OTA-induced oxidative stress and apoptosis | Abdel et al. [113] |
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Khoi, C.-S.; Chen, J.-H.; Lin, T.-Y.; Chiang, C.-K.; Hung, K.-Y. Ochratoxin A-Induced Nephrotoxicity: Up-to-Date Evidence. Int. J. Mol. Sci. 2021, 22, 11237. https://doi.org/10.3390/ijms222011237
Khoi C-S, Chen J-H, Lin T-Y, Chiang C-K, Hung K-Y. Ochratoxin A-Induced Nephrotoxicity: Up-to-Date Evidence. International Journal of Molecular Sciences. 2021; 22(20):11237. https://doi.org/10.3390/ijms222011237
Chicago/Turabian StyleKhoi, Chong-Sun, Jia-Huang Chen, Tzu-Yu Lin, Chih-Kang Chiang, and Kuan-Yu Hung. 2021. "Ochratoxin A-Induced Nephrotoxicity: Up-to-Date Evidence" International Journal of Molecular Sciences 22, no. 20: 11237. https://doi.org/10.3390/ijms222011237