The Interplay between Uremic Toxins and Albumin, Membrane Transporters and Drug Interaction
Abstract
:1. Introduction
2. Protein-Bound Uremic Toxins (PBUTs)
2.1. Indoxyl Sulfate (IS)
2.2. p-Cresyl Sulfate (PCS)
2.3. Indole-3-Acetic Acid (IAA)
2.4. 3-Carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF)
3. Interaction between Uremic Toxins and Albumin
4. Cell Membrane Transporters of Uremic Toxins
4.1. Organic Anions Transporters (OATs)
4.2. Organic Cation Transporters (OCTs)
4.3. Organic Anion-Transporting Polypeptides (OATPs)
4.4. Inorganic Phosphate Transporters (PiTs)
4.5. Multidrug and Toxin Extrusion (MATE)
4.6. Breast Cancer Resistance Protein (BCRP)
4.7. Multidrug Resistance-Associated Proteins (MRPs)
5. Final Considerations
Author Contributions
Funding
Conflicts of Interest
References
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Protein | Gene | Tissue Distribution | Uremic Toxin Interaction | Drug Interaction |
---|---|---|---|---|
OAT1 | SLC22A6 | Kidney | PCS, IS, kynurenic acid, hippuric acid | Probenecid, β-lactam antibiotics, nonsteroidal anti-inflammatory drugs |
OAT2 | SLC22A7 | Kidney, liver | Creatinine | |
OAT3 | SLC22A8 | Kidney | PCS, IS, kynurenic acid, hippuric acid | Probenecid, ciprofloxacin, β-lactam antibiotics, nonsteroidal anti-inflammatory drugs |
OCT2 | SLC22A2 | Kidney | Creatinine, TMAO, methylguanidine, guanidine, putrescine | Metformin, cisplatin, cimetidine, vandetanib, trimethoprim |
OCT3 | SLC22A3 | Choroid plexus, skeletal muscle, placenta, kidney | Creatinine | |
OATP4C1 | SLCO4C1 | Kidney | ADMA | OATP4C1 expression is modulated by statins |
PiT-1 | SLC20A1 | Endothelial cells, intestine, bones | Pi | |
PiT-2 | SLC20A2 | Endothelial cells, intestine, bones, kidney | Pi | |
NaPi2B | SLC34A2 | Intestine | Pi | Nicotinic acid and nicotinamide inhibit NaPi2B expression |
MATE1 | SLC47A1 | Kidney, liver, heart | TMAO, creatinine, guanidine | Trimethoprim, trospium, ondansetron |
MATE2-K | SLC47A2 | Kidney | Creatinine, guanidine | |
BCRP | ABCG2 | Kidney, intestine, blood vessels, placenta | PCS, IS, kynurenic acid, TMAO, uric acid | Febuxostat |
MRP2 | ABCC2 | Kidney, liver, intestine, brain capillary endothelium | TMAO | Methotrexate, nonsteroidal anti-inflammatory drugs |
MRP4 | ABCC4 | Kidney, liver, intestine, brain capillary endothelium | TMAO | Methotrexate, nonsteroidal anti-inflammatory drugs |
Protein | Experimental Model | Main Findings |
---|---|---|
OAT1 | OAT1-expressing HEK293 cells | Cell uptake of PCS [100] |
Slc22a6-knockout mice | Increased plasma levels of PCS, IS, and kynurenine [89] | |
Slc22a6-knockout mice | Increased plasma levels of PCS, IS, and IAA [88] | |
Rats | Renal uptake of hippurate, IAA, and IS [92] | |
Nephrectomized rats | Decreased protein levels in the kidneys [83] | |
Nephrectomized rats | Decreased protein and mRNA levels in the kidneys [84] | |
Nephrectomized rats | Decreased protein levels in the kidneys [86] | |
Nephrectomized rats | No differences in protein levels in the kidney [85] | |
Nephrectomized rats treated with IS | Increased protein levels in the renal tubules [87] | |
OAT3 | OAT3-expressing HEK293 cells | Cell uptake of PCS [100] |
Rats and Oat3-expressing oocytes | Renal uptake of IS [94] | |
Slc22a8-knockout mice | Increased plasma levels of PCS, IS, CMPF, and TMAO [89] | |
Rats | Renal uptake of IS and CMPF [92] | |
Rats treated with IS | Decreased the renal clearance of IS through inhibition on the OAT3-mediated transport with ciprofloxacin [107] | |
Nephrectomized rats | Decreased protein levels in the kidneys [86] | |
Nephrectomized rats | No differences in protein levels in the kidney [85] | |
OAT1/3 | HK-2 cells and rat renal cortical slices | Cell uptake of PCS, which was inhibited with probenecid, an inhibitor of OATs [93] |
Endothelial cells | Cell uptake of PCS and IS, which was inhibited with probenecid [101] | |
Endothelial cells | Probenecid attenuated the inductive effects of IS on the expression of E-selectin and monocytic cell adhesion [103] | |
Endothelial cells and aortic smooth muscle cells | Probenecid reversed the inductive effect of PCS on MCP-1 expression in endothelial cells and on the expression of osteogenic differentiation genes in aortic smooth muscle cells [102] | |
Osteoblasts | Probenecid restored IS-induced effects on cell viability and ROS levels [104] | |
Myoblast cells | Probenecid reversed IS-induced effects on ROS levels and inflammatory cytokine expression [106] | |
Human subjects | Subjects treated with probenecid had elevated IS and kynurenine levels [111] | |
Kidney transplant patients | Increased plasma levels of IS, PCS and IAA in patients with a prescription of at least one drug which inhibits OAT1/OAT3 [112] | |
OAT2 | MDCKII cells | Cell uptake of creatinine [113] |
OAT2-transfected HEK cells | Cell uptake of creatinine [114] | |
OCT2 | ciPTEC cells | Uptake of cationic uremic toxins, such as guanidine, methylguanidine, and putrescine [116] |
HEK293 cells | Cell uptake of guanidine compounds [118] | |
HEK293 cells | Cell uptake of creatinine [120] | |
MDCKII and HEK cells | Cell uptake of TMAO and transcellular transport [125] | |
HEK293 cells | Cell uptake of putrescine [124] | |
OCT2-expressing HEK cells | Inhibited by creatinine, dimethylamine, malondialdehyde, trimethylamine, homocysteine, indoxyl-β-d-glucuronide, and glutathione disulfide [123] | |
HEK293 cells | Vandetanib inhibited the uptake of creatinine [129] | |
Slc22a2/1-double knockout mice and HeLa cells | Increased plasma levels of TMAO. In vitro, TMAO transport [110] | |
Slc22a2/1-double knockout mice and Oct2-transfected HEK293 cells | Increased plasma levels of TMAO. In vitro and In vitro, TMAO uptake [126] | |
Nephrectomized rats | Decreased protein levels in the kidney [85] | |
Patients with CKD and nephrectomized rats | Decreased protein levels in the kidney [130] | |
Patients with cancer undergoing treatment with cisplatin and HEK293 cells | Increased serum levels of creatinine. In vitro, creatinine uptake [128] | |
Patients with end-stage renal disease | Relationship between SLC22A2 polymorphisms and phenotypes of net tubular creatinine secretion [119] | |
OATP4C1 | MDCK cells | Transport of ADMA [141] |
HEK293 cells | Cell uptake of ADMA [140] | |
HK-2 cells and rats treated with IS | IS reduced the OATP4C1 expression [143] | |
Transgenic mice overexpressing OATP4C1 in the kidneys | Decreased plasma levels of ADMA, guanidino succinate, and trans-aconitate [142] | |
Nephrectomized rats | Decreased mRNA levels in the kidney [144] | |
OATP1B1/3 | Human hepatocytes and HEK293 cells | Decreased mRNA levels in cells exposed to uremic plasma. Inhibited by uremic toxin mix (IS, indole acetate, hippuric acid, and CMPF) [145] |
PiT-1/2 | Endothelial cells | Inhibition and knockout of PiT-1 reduced intracellular Pi concentrations [154] |
PiT-1-expressing oocytes | Pi transport [150] | |
VSMCs | Uptake of Pi, which at high levels induces osteochondrogenic differentiation of VSMCs [155] | |
Human smooth muscle cells | Cell uptake of Pi [156] |
Protein | Experimental Model | Main Findings |
---|---|---|
MATE1 | HEK293 cells | Creatinine and guanidine as substrates [159] |
HEK293 cells | Creatinine as substrate [161] | |
MDCKII and HEK cells | Transport of TMAO, which was suppressed by trimethoprim [125] | |
Nephrectomized rats | Decreased protein levels in the kidneys [164] | |
MATE2-K | HEK293 cells | Creatinine and guanidine as substrates [159] |
BCRP | ciPTEC cells | BCRP inhibition increased intracellular PCS levels [174] |
HeLa cells | TMAO transport [110] | |
Membrane vesicles from MRP4-overexpressing HEK cells | Inhibited by hippuric acid, IS, and kynurenic acid [178] | |
Caco-2 cells | Urate transport. IS reduced BCRP expression [179] | |
Endothelial cells | Uric acid decreased the BCRP protein levels [183] | |
Abcg2-knockout mice with adenine-induced CKD and membrane vesicles from HEK293A cells | Increased plasma levels and decreased renal elimination of IS. In vitro, IS transport [175] | |
Abcg2-knockout mice and HEK293 cells | Kynurenic acid as substrate [177] | |
Abcg2-knockout mice | Increased plasma levels and low urine levels of IS [175] | |
Adenine-induced acute renal failure rats | Febuxostat, an BCRP inhibitor, decreased renal clearance of the IS [97] | |
Nephrectomized rats | Decreased mRNA levels in the kidney [172] | |
Nephrectomized rats | Decreased protein and mRNA levels in the kidney [173] | |
MRP2 | HeLa cells | Performs cellular efflux of TMAO [110] |
Nephrectomized rats | Increased protein and mRNA levels in the kidneys [84] | |
Nephrectomized rats | Increased mRNA levels in the liver and the kidneys [172] | |
Nephrectomized rats | Decreased protein levels in the intestine [188] | |
MRP4 | Membrane vesicles from MRP4-overexpressing HEK cells | Inhibited by IS, hippuric acid, kynurenic acid, IAA, and phenylacetic acid [178] |
ciPTEC cells | Inhibited by PCS and p-cresyl glucuronide [174] | |
HeLa cells | Performs cellular efflux of TMAO [110] | |
Nephrectomized rats | Increased protein and mRNA levels in the kidneys [84] | |
Nephrectomized rats | No differences in mRNA levels in the kidney, liver, and intestine [172] | |
Nephrectomized rats | No differences in mRNA levels in the kidney and the liver [189] |
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Cunha, R.S.d.; Azevedo, C.A.B.; Falconi, C.A.; Ruiz, F.F.; Liabeuf, S.; Carneiro-Ramos, M.S.; Stinghen, A.E.M. The Interplay between Uremic Toxins and Albumin, Membrane Transporters and Drug Interaction. Toxins 2022, 14, 177. https://doi.org/10.3390/toxins14030177
Cunha RSd, Azevedo CAB, Falconi CA, Ruiz FF, Liabeuf S, Carneiro-Ramos MS, Stinghen AEM. The Interplay between Uremic Toxins and Albumin, Membrane Transporters and Drug Interaction. Toxins. 2022; 14(3):177. https://doi.org/10.3390/toxins14030177
Chicago/Turabian StyleCunha, Regiane Stafim da, Carolina Amaral Bueno Azevedo, Carlos Alexandre Falconi, Fernanda Fogaça Ruiz, Sophie Liabeuf, Marcela Sorelli Carneiro-Ramos, and Andréa Emilia Marques Stinghen. 2022. "The Interplay between Uremic Toxins and Albumin, Membrane Transporters and Drug Interaction" Toxins 14, no. 3: 177. https://doi.org/10.3390/toxins14030177
APA StyleCunha, R. S. d., Azevedo, C. A. B., Falconi, C. A., Ruiz, F. F., Liabeuf, S., Carneiro-Ramos, M. S., & Stinghen, A. E. M. (2022). The Interplay between Uremic Toxins and Albumin, Membrane Transporters and Drug Interaction. Toxins, 14(3), 177. https://doi.org/10.3390/toxins14030177