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2017 ; 7
(1
): 4939
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gab.com Text
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Key Role for the Organic Anion Transporters, OAT1 and OAT3, in the in vivo
Handling of Uremic Toxins and Solutes
#MMPMID28694431
Wu W
; Bush KT
; Nigam SK
Sci Rep
2017[Jul]; 7
(1
): 4939
PMID28694431
show ga
In vitro data indicates that the kidney proximal tubule (PT) transporters of
uremic toxins and solutes (e.g., indoxyl sulfate, p-cresol sulfate, kynurenine,
creatinine, urate) include two "drug" transporters of the organic anion
transporter (OAT) family: OAT1 (SLC22A6, originally NKT) and OAT3 (SLC22A8).
Here, we have examined new and prior metabolomics data from the Oat1KO and
Oat3KO, as well as newly obtained metabolomics data from a "chemical double"
knockout (Oat3KO plus probenecid). This gives a picture of the in vivo roles of
OAT1 and OAT3 in the regulation of the uremic solutes and supports the centrality
of these "drug" transporters in independently and synergistically regulating
uremic metabolism. We demonstrate a key in vivo role for OAT1 and/or OAT3 in the
handling of over 35 uremic toxins and solutes, including those derived from the
gut microbiome (e.g., CMPF, phenylsulfate, indole-3-acetic acid). Although it is
not clear whether trimethylamine-N-oxide (TMAO) is directly transported, the
Oat3KO had elevated plasma levels of TMAO, which is associated with
cardiovascular morbidity in chronic kidney disease (CKD). As described in the
Remote Sensing and Signaling (RSS) Hypothesis, many of these molecules are
involved in interorgan and interorganismal communication, suggesting that uremia
is, at least in part, a disorder of RSS.
|Animals
[MESH]
|Biomarkers
[MESH]
|Gene Knockdown Techniques
[MESH]
|Kidney Tubules, Proximal/metabolism
[MESH]
|Metabolome
[MESH]
|Metabolomics
[MESH]
|Mice
[MESH]
|Organic Anion Transport Protein 1/genetics/*metabolism
[MESH]