# Endocytic Pathway Dysfunction in Dent Disease

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $464,592

## Abstract

Abstract
Tubular proteinuria resulting from impaired endocytic uptake of filtered proteins by the kidney
proximal tubule (PT) is a common feature of early kidney dysfunction that poses a significant risk
for development of end-stage renal disease. This proposal aims to understand the mechanistic
basis of Dent disease, a progressive genetic disorder characterized by tubular proteinuria that is
caused by mutations in the 2Cl-/H+ exchanger ClC-5. Enhanced degradation of megalin, a
multiligand co-receptor that binds to filtered proteins, is thought to underlie the tubular proteinuria in
Dent disease, however, the step in trafficking that is affected is unknown, and the contribution of pH
vs. Cl- homeostasis to the disease phenotype is disputed. We will utilize a combination of genetic,
morphological, mathematical modeling, and biochemical approaches to accomplish the following
aims: (1) identify the step(s) in membrane traffic that are impaired in ClC-5 knockdown PT cells; (2)
determine the molecular mechanism that links loss of ClC-5 to reduced megalin expression; and (3)
identify therapeutic targets for restoring megalin expression and function in a mouse model of Dent
disease.

## Key facts

- **NIH application ID:** 10125152
- **Project number:** 5R01DK125049-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Ora A Weisz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $464,592
- **Award type:** 5
- **Project period:** 2020-03-10 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10125152

## Citation

> US National Institutes of Health, RePORTER application 10125152, Endocytic Pathway Dysfunction in Dent Disease (5R01DK125049-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10125152. Licensed CC0.

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