Gut-derived uremic toxin handling in vivo requires OAT-mediated tubular secretion in chronic kidney disease
Kevin T. Bush, Prabhleen Singh, Sanjay K. Nigam
Kevin T. Bush, Prabhleen Singh, Sanjay K. Nigam
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Research Article Metabolism Nephrology

Gut-derived uremic toxin handling in vivo requires OAT-mediated tubular secretion in chronic kidney disease

Abstract

The role of the renal organic anion transporters OAT1 (also known as SLC22A6, originally identified as NKT) and OAT3 (also known as SLC22A8) in chronic kidney disease (CKD) remains poorly understood. This is particularly so from the viewpoint of residual proximal tubular secretion, a key adaptive mechanism to deal with protein-bound uremic toxins in CKD. Using the subtotal nephrectomy (STN) model, plasma metabolites accumulating in STN rats treated with and without the OAT inhibitor, probenecid, were identified. Comparisons with metabolomics data from Oat1-KO and Oat3-KO mice support the centrality of the OATs in residual tubular secretion of uremic solutes, such as indoxyl sulfate, kynurenate, and anthranilate. Overlapping our data with those of published metabolomics data regarding gut microbiome–derived uremic solutes — which can have dual roles in signaling and toxicity — indicates that OATs play a critical role in determining their plasma levels in CKD. Thus, the OATs, along with other SLC and ABC drug transporters, are critical to the movement of uremic solutes across tissues and into various body fluids, consistent with the remote sensing and signaling theory. The data support a role for OATs in modulating remote interorganismal and interorgan communication (gut microbiota–blood-liver-kidney-urine). The results also have implications for understanding drug-metabolite interactions involving uremic toxins.

Authors

Kevin T. Bush, Prabhleen Singh, Sanjay K. Nigam

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Figure 1

Subtotal nephrectomy alters kidney function, leading to differences in plasma metabolite profiles.

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Subtotal nephrectomy alters kidney function, leading to differences in p...
(A) Box-and-whisker plots illustrating the effects of subtotal nephrectomy on the glomerular filtration rate (GFR; left side of graph), as measured by ml/min of inulin clearance, and tubular secretion (right side), as measured by the clearance of para-aminohippurate (PAH). Two weeks after STN surgery there was a significant reduction in both GFR (~50%; *P ≤ 0.05) and tubular secretion (~50%; *P ≤ 0.05) in the STN animals (white rectangles) compared with the sham-operated animals (gray rectangles). Box plots were generated using the functionalities of BoxPlotR (92) (5 animals were used for each experimental group; a 2-tailed Student’s t test was used to determine statistical significance; a P value less than 0.05 was considered significant). (B) Box-and-whisker plots of the changes in amino acid concentrations following STN. The plasma concentration of tryptophan was significantly reduced following STN. Additionally, there were significant reductions in the plasma ratios of arginine to citrulline (*P ≤ 0.05). Black cross in each box represent the mean; solid black center lines indicate the median; open circles represent the individual data points; box limits indicate the 25th and 75th percentiles as determined by R software; whiskers extend 1.5 times the interquartile range from the 25th and 75th percentiles; outliers are represented by dots (92) (5 measures of plasma concentration were used for each experimental group; a 2-tailed Student’s t test was used to determine statistical significance; a P value less than 0.05 was considered significant).