Abstract
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.
Highlights
IntroductionUremic toxins have been divided into the following subgroups of compounds: (1) small water-soluble, non-protein-bound (e.g., urea); (2) small protein-bound (e.g., indoxyl sulfate); and (3) middle molecules (mainly small and large peptides)[1, 2]
Uremic toxins have been divided into the following subgroups of compounds: (1) small water-soluble, non-protein-bound; (2) small protein-bound; and (3) middle molecules[1, 2]
While adding a few molecules which accumulate in the plasma of the Oat1KO, the metabolomics analysis of the plasma from the Oat1KO largely agreed with previous studies (Table 1)[12, 13]
Summary
Uremic toxins have been divided into the following subgroups of compounds: (1) small water-soluble, non-protein-bound (e.g., urea); (2) small protein-bound (e.g., indoxyl sulfate); and (3) middle molecules (mainly small and large peptides)[1, 2]. The importance of water-soluble and protein-bound toxins has received considerable attention over the past several years[1]. Many of these are small, charged molecules whose uptake from the plasma and excretion via the kidney is mediated by transport proteins expressed on proximal tubule (PT) cells[3,4,5]. Previous targeted and untargeted limited metabolomics analyses of the Oat1KO and Oat3KO animals, albeit limited in that some were performed with older methods, instruments and databases, revealed significant alterations (up in plasma, down in urine) in the concentration of several uremic toxins and/or uremic retention solutes, including indoxyl sulfate, kynurenine, www.nature.com/scientificreports/. Using a more comprehensive metabolomics analysis, levels of over 90 reported uremic toxins and uremic retention solutes were analyzed from the plasma of Oat1KO and Oat3KO animals, as well as from Oat3KO mice treated with probenecid, an inhibitor of OAT-mediated transport (“chemical double knockouts”)[23]
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