# The Role in OAT1 in Uremia

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $610,305

## Abstract

OAT1 IN UREMIA
PROJECT SUMMARY/ABSTRACT
Organic anion transporter 1 (OAT1/SLC22A6), discovered by us (NKT), is the prototypical kidney organic anion
(PAH) transporter responsible for the transport of many drugs (e.g., diuretics, antivirals, NSAIDs). Based on
our in vivo studies of the Oat1 knockout mouse during the last project period and in vitro studies by us and
others, OAT1 is now believed to be a central component of a proximal tubule sensing and elimination
mechanism for gut microbe products and uremic toxins. Furthermore, recent data from our lab in rodents, as
well as human studies by others, indicates that OAT1-dependent function is critical for residual kidney function
in CKD. However, what is truly remarkable from our metabolomics and transcriptomics studies is the degree to
which OAT1, which is almost exclusively expressed in the kidney, regulates systemic metabolism--beyond gut
microbe products and uremic toxins. For example, it regulates many signaling lipids, citric acid cycle
intermediates, bile acids, and vitamins/cofactors. Indeed, OAT1 may be the renal gene with the broadest
effects on systemic metabolism. Although CKD is a multi-factorial disease, one of these factors is the
metabolic consequence of the gradual loss of OAT1-dependent sensing and elimination as proximal tubule
function declines. Thus, we hypothesize that, in CKD, the normal functioning of OAT1-mediated protein-bound
metabolite sensing and signaling in the proximal tubule is severely disrupted--leading to major disruptions in
small molecule metabolism and signaling. This is because of the endogenous role of OAT1 as a central
component of a larger metabolic network involving gut microbe-derived metabolites, some of which participate
in uremic toxicity in severe kidney disease but which also impact tryptophan and lipid metabolism as well as
other metabolic processes. Using the latest approaches to integration of large omics datasets and a
particularly novel multi-scale metabolic reconstruction approach (combining Recon3D with a genome-scale
microbiome reconstruction), we will define the pathways in Oat1 KO mice under conditions in which: a) the gut
microbiome is present or depleted; and b) kidney function is compromised. At the end, we will have fully
analyzed combinations of Oat1 KO vs WT, healthy vs depleted gut microbiome, and sham operation vs 5/6
nephrectomy, as sampled in the serum, kidney, liver and feces. This will settle (in mice) the relative importance
of each altered state on levels of uremic toxins, on biochemical pathways, and on overall multi-scale metabolic
impact as determined by genome-scale metabolic reconstruction for each of the conditions. A portion of the
omics data has already been obtained (KO effect, partial gut microbe effect). This project will thus produce a
validated detailed map of OAT1-centered metabolism in normal physiology and in diseased states, possibly the
first of its kind for any multi-specific “drug” transporter (Nigam, Nat...

## Key facts

- **NIH application ID:** 10684232
- **Project number:** 5R01DK109392-06
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** SANJAY K NIGAM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $610,305
- **Award type:** 5
- **Project period:** 2017-01-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10684232

## Citation

> US National Institutes of Health, RePORTER application 10684232, The Role in OAT1 in Uremia (5R01DK109392-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10684232. Licensed CC0.

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