# PODOCYTE ENDOPLASMIC RETICULUM STRESS AND NEPHROTIC SYNDROME

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $305,000

## Abstract

Abstract
 Nephrotic syndrome (NS) is characterized by heavy proteinuria and increased risk of loss of kidney
function. It causes serious morbidity and high mortality, accounting for 15% of prevalent end-stage renal
disease at an annual cost of more than $3 billion in the US. There is no effective treatment for most cases of
NS caused by genetic mutations. Our research has been focused on a monogenic form of NS caused by a
missense mutation (C321R) of LAMB2, one of the most commonly mutated genes in NS. Laminin 2 encoded
by LAMB2 is a component of laminin-521 ( 5 2 1), the major laminin trimer of the glomerular basement
membrane (GBM). Using our established knockout/transgenic mouse model, we have found that podocyte
endoplasmic reticulum (ER) stress and subsequent defective secretion of misfolded C321R-LAMB2 from
podocytes to the GBM lead to proteinuria. Furthermore, we have recently discovered an ER soluble factor that
promotes the survival of ER-stressed podocytes.
 The overall goals of this proposal are to delineate molecular mechanisms regulating important death and
survival pathways activated by the C321R-LAMB2 mutation-induced podocyte ER stress, to determine the
contribution of podocyte ER stress in NS patients carrying putative deleterious missense variants, and to
investigate novel treatment strategies for genetic forms of NS. To accomplish our research goals, we will utilize
mouse genetic models and access two major human NS cohorts, Nephrotic Syndrome Study Network
(NEPTUNE) and the Washington University Kidney Translational Research Core (WU KTRC). We have
assembled an interdisciplinary team including multiple co-investigators and collaborators with the required
expertise in pioneering ER stress research, human and mouse genetics, next generation sequencing, and high
throughput screening.
 The proposed study will help us classify NS patients based on underlying molecular mechanisms, stratify
disease risk, and discover highly-targeted treatments for NS patients caused by podocyte ER dysfunction.

## Key facts

- **NIH application ID:** 9930584
- **Project number:** 5R01DK105056-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Ying Maggie Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $305,000
- **Award type:** 5
- **Project period:** 2017-08-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9930584

## Citation

> US National Institutes of Health, RePORTER application 9930584, PODOCYTE ENDOPLASMIC RETICULUM STRESS AND NEPHROTIC SYNDROME (5R01DK105056-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9930584. Licensed CC0.

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