# Renal Secretion of Drugs as a Function of Developmental Stage in Pediatric Models

> **NIH NIH P50** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $162,591

## Abstract

PROJECT 3 SUMMARY/ABSTRACT
Several drugs, including NSAIDSs and methotrexate, used to treat pediatric inflammatory conditions are
dependent on renal drug transporters for some of their elimination. Anakinra, also used to treat inflammatory
conditions, may alter the renal transporter expression or post-translational processing. In the dynamic setting
of the postnatal developing kidney, when expression of the most relevant drug transporters--the organic anion
transporters OAT1 and OAT3--is rapidly changing, the effects of these inflammatory therapies on renal drug
secretion is likely to be quite complex. These effects will be hard to unravel without gaining a clear
understanding of how drug transporter expression relates to apical-basolateral polarization so that optimal
vectorial drug transport occurs (e.g., the capacity of the renal proximal tubule to transport drugs (methotrexate)
from plasma to urine).. Here, we focus on the renal drug transporters OAT1 (originally discovered by our
group) and OAT3, as well as other drug transporters during postnatal and juvenile maturation of the kidney.
Specifically, we will address how message and protein levels, subcellular localization, apical-basolateral
polarization, and the function of these transporters is regulated during the developmental stages of kidney
maturation. A detailed analysis of the spatio-temporal coordination of these processes in relation to renal
secretion will also be very helpful for improving pediatric physiologically-based pharmacokinetic model
systems. In our studies, functional maturation will be assessed by measurement of transport of labeled
substrates. We will employ a combination of in vitro, ex vivo and in vivo animal studies (using wild type and
knockouts) and, with an eye to translational studies (in collaboration with other RPDP investigators), human
progenitor stem cell (hPSC)-derived renal organoids, which differentiate to the point of substantial expression
of OATs and other drug transporters. Focusing on drugs used for inflammatory conditions, we aim to address
the following questions: SA1) What is the temporal relationship of OAT1, OAT3 and other drug transporter
expression, post-transcriptional processing, and apical-basolateral membrane sorting to the acquisition of drug
transport capacity during proximal tubule maturation? SA2) Can renal organoids derived from human iPS cells
be used as a model for understanding the regulation of OATs and other drug transporters in the context of
renal secretion (as a function of the aforementioned cell biological processes)? We expect to generate a great
deal of time series omics, microscopic and functional data. Importantly, we have considerable experience in
systems biology and computational data integration--and we have the support of expert collaborators and
cores. Consistent with the Pediatric Transporter Working Group Recommendations, these studies will:
“Investigate basic developmental mechanisms regulating transporter exp...

## Key facts

- **NIH application ID:** 9970241
- **Project number:** 5P50HD090259-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** SANJAY K NIGAM
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $162,591
- **Award type:** 5
- **Project period:** 2016-09-20 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970241

## Citation

> US National Institutes of Health, RePORTER application 9970241, Renal Secretion of Drugs as a Function of Developmental Stage in Pediatric Models (5P50HD090259-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9970241. Licensed CC0.

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