# Juxta-glomerular cells serve as glomerular epithelial cell progenitors in glomerular disease

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2022 · $593,267

## Abstract

PROJECT SUMMARY
Chronic kidney disease (CKD) is increasing in the US, now impacting at least one in ten people. CKD typically
results in end-stage kidney disease (ESRD), that requires either dialysis or kidney transplantation. Proteinuric
glomerular diseases are the major cause of CKD and ESRD and are generally caused by progressive
podocyte loss followed by glomerular scarring. Because podocytes are terminally differentiated epithelial cells
they cannot regenerate. Therefore, following loss in disease, partial or complete podocyte replacement relies
on trans-differentiation of adjacent progenitor cells. These include parietal epithelial cells, and cells of the renin
lineage (CoRL), the latter being the focus of this competitive renewal. Unfortunately, endogenous podocyte
replacement is often not robust enough to assure protection. Given this situation, and to address the unmet
need to augment podocyte replacement through discovery of new targets, our long-term goal is to understand
the mechanisms underlying podocyte regeneration, and identify therapeutic options towards restoring podocyte
numbers and preventing glomerular scaring. We recently reported that CoRL are pluri-potent progenitors that
can trans-differentiate towards podocytes, parietal epithelial cells, mesengial cells and pericytes. We have also
shown that the transcription factor Wt1 is a critical player and is necessary for CoRL proliferation and
migration, and its trans-differentiation to a podocyte fate. However, the precise molecular mechanism(s)
underlying this CoRL biology are still poorly understood. To resolve this, the overall objective of this application
is to investigate the mechanisms and pathways to augment CoRL progenitor function and its trans-
differentiation into podocytes. Our central hypothesis is that we can ramp up the ability of these CoRL to
become podocytes, and replace those lost by modulating distinct signaling systems such as Wnt signaling. To
test this, we will pursue two Specific Aims: (1) Test the hypothesis that the progenitor capacity of cells of renin
lineage (CoRL) to trans-differentiate to a podocyte fate is governed by the balance of WT1 and Wnt signaling,
and (2) Identify pathways underlying the pluripotency of cells of renin lineage towards different adult kidney cell
type fates in glomerular diseases. The approach is innovative as it is based on a unique ability to culture CoRL
ex vivo, innovative bioengineered cell culture devices, a newly developed dual-reporter mice to definitively
trace CoRL-podocyte trans-differentiation, and Quality-by-Design (QbD)-based methodologies to identify
complex and robust culture conditions. The research is significant as it provides an in depth understanding of
the potential of CoRL to differentiate into multiple kidney cell types even in adults. In addition, it will advance
the field by identifying potentially novel therapeutic options towards restoring podocyte numbers, and in doing
so, preventing and even re...

## Key facts

- **NIH application ID:** 10436216
- **Project number:** 5R01DK097598-09
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Stuart James Shankland
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $593,267
- **Award type:** 5
- **Project period:** 2014-08-05 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436216

## Citation

> US National Institutes of Health, RePORTER application 10436216, Juxta-glomerular cells serve as glomerular epithelial cell progenitors in glomerular disease (5R01DK097598-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10436216. Licensed CC0.

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