Table 2.
Studies that address the relationship between cellular influx transporters and uremic toxins in chronic kidney disease.
| 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] |
Abbreviations: ADMA, asymmetric dimethylarginine; ciPTEC, immortalized proximal tubule epithelial cells; CMPF, 3-Carboxy-4-methyl-5-propyl-2-furanpropionate; HEK, human embryonic kidney cells; HK-2, human proximal tubular cells; IAA, indole-3-acetic acid; IS, indoxyl sulfate; MCP-1, monocyte chemoattractant protein-1; MDCKII, Madin–Darby canine kidney II cells; PCS, p-cresyl sulfate; Pi, inorganic phosphate; ROS, reactive oxygen species; TMAO, trimethylamine-N-oxide; VSMCs, vascular smooth muscle cells.