# The Role of OAT1 in Uremia

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $348,750

## Abstract

PROJECT SUMMARY/ABSTRACT
OAT1 (SLC22A6) is the prototypical kidney organic anion (PAH) transporter. It is responsible for the transport
of many drugs (eg. antibiotics, diuretics, antivirals, NSAIDs) and toxins (organic mercurials). We identified the
transporter (as NKT); we also first published the Oat1 knockout (Oat1KO) and phenotypes. Our recent data
indicates that OAT1 is central to many systemic and proximal tubule metabolic processes. Oat1KO
metabolomics data indicates OAT1 may be the key in vivo transporter of uremic toxins accumulating in renal
insufficiency and chronic kidney disease (CKD). Altering OAT1 function and/or expression may ameliorate the
metabolic changes in states of compromised renal function. We hypothesize that the “true” physiological role of
OAT1 is as a central component of a larger metabolic network involved in normal physiological and
pathophysiological processes, and OAT1 exerts a modulatory effect on metabolic diseases (eg. uremic
syndrome) via this network. We will define the OAT1-centered network in detail. Specifically: 1) We will
construct the OAT1-centered metabolic network through metabolic reconstruction of transcriptomics and
metabolomics data from the Oat1KO (using the systems biology techniques described). We should be able to
clearly delineate the pathways by which OAT1 regulates normal metabolism by: a) overlaying ligand-based
pharmacophore models (in-hand) upon this preliminary reconstructed OAT1-centered network, and b) testing
of “hits” in wet lab transport assays. 2) We will then determine what role the validated OAT1-centered
metabolic network (and key pathways within it) plays in the metabolic alterations of renal insufficiency using
rodent subtotal nephrectomy models and human CKD metabolomics data. We seek to build a very detailed,
fully validated, network of >200 metabolites and reactions that makes predictions that can be evaluated in
pathophysiological models and disease states. In response to previous criticisms, we have revised the
proposal, particularly with respect to the disease model—and included an expert collaborator from the UCSD
O’Brien Center to help with the studies and interpretation. Although the project was considered ambitious, we
emphasize the huge amount of preliminary data and “in house” expertise. The team of investigators has
expertise in transport, metabolism, network biology, epidemiology of kidney disease, animal models, and
statistical analysis of large data sets. This project will thus produce a validated detailed map of OAT1-centered
metabolism in normal physiology and a diseased state, possibly the first of its kind for any multispecific “drug”
transporter (Nigam, Nature Reviews Drug Discovery, 2015). The studies could lead to design of strategies for
improving the metabolic abnormalities in CKD by affecting OAT1 function or expression; they will also help
predict how OAT1-transported drugs affect metabolism in kidney disease.

## Key facts

- **NIH application ID:** 9844466
- **Project number:** 5R01DK109392-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** SANJAY K NIGAM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $348,750
- **Award type:** 5
- **Project period:** 2017-01-15 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9844466

## Citation

> US National Institutes of Health, RePORTER application 9844466, The Role of OAT1 in Uremia (5R01DK109392-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9844466. Licensed CC0.

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