# Impact of Cadmium Exposure on Transporter Function and Drug Disposition in the Kidney

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2024 · $363,710

## Abstract

PROJECT SUMMARY/ABSTRACT
 The heavy metal cadmium (Cd) is currently ranked 7th on the 2019 US Agency for Toxic Substances and
Disease Registry (ATSDR) and listed as one of Priority Pollutants by US Environmental Protection Agency
(EPA). Although intoxication by high levels of Cd exposure is rarely seen nowadays, chronic low levels of Cd
exposure is still a major health concern as Cd is a cumulative metal with an extremely long biological half-life of
10-30 years in human body. Cd exposure has been associated with increased incidence of multiple diseases.
Strikingly, little is known whether chronic Cd exposure would affect the disposition of drugs that are used to treat
diseases. Renal transporter proteins involve in drug disposition by mediating drug transport across tubular cells
and particularly proximal tubules. Coordinated transcellular transport by uptake transporters, such as organic
cation transporters (OCTs) and organic anion transporters (OATs) in the basolateral membrane in concert with
efflux transporters, such as multidrug and toxin extrusion proteins (MATEs) and multidrug resistance-associated
proteins (MRPs) in the apical membrane of tubular cells, is believed to be an essential system for renal
disposition of cationic and anionic drugs, respectively. Our recent publications and current preliminary results
indicate a broad effect by chronic Cd exposure on renal transporters including OCTs, MATEs, OATs and MRPs.
However, the detail mechanism of transporter regulation by Cd and its broad impact on drug disposition and
response remain to be illustrated. We hypothesize that chronic Cd exposure could alter renal transporter
function, resulting in alteration in drug disposition and toxicity in the kidney. To test this hypothesis, we propose
to conduct research with three specific Aims. Firstly, by using a variety of cellular and molecular assays, along
with proteomic approach, we will uncover a molecular mechanism by which chronic Cd exposure enhances the
translocation of OCT and OAT uptake proteins from the cytoplasmic pool to cell membrane and consequently
increase the cellular accumulation of small molecules that are the substrates of these transporters (Aim 1). Most
clinical used drugs are either organic cations or organic anions. We then propose to demonstrate the impact of
Cd exposure on the disposition of cationic drugs by investigating the effects of Cd exposure on OCT and MATE
expression in mouse kidney tissues and human renal cells, and particularly the impact on cisplatin disposition
and nephrotoxicity using Oct1/2- and Mate1-deficinet mice (Aim 2). Lastly, the effects of chronic Cd exposure
on expression of the anionic drug transporters OATs and MRPs will be characterized in mouse kidney tissues
and human renal cells, and specifically Cd impact on the disposition and nephrotoxicity of the antiviral tenofovir
will be studied with Oat1/3-, Mrp4-deficient mice and OAT pharmacological inhibition (Aim 3). Successful
completion of t...

## Key facts

- **NIH application ID:** 10808928
- **Project number:** 5R01ES033301-03
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Yan Shu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $363,710
- **Award type:** 5
- **Project period:** 2022-05-24 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10808928

## Citation

> US National Institutes of Health, RePORTER application 10808928, Impact of Cadmium Exposure on Transporter Function and Drug Disposition in the Kidney (5R01ES033301-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10808928. Licensed CC0.

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