# Glomerular Cell-Cell Crosstalk and Injury

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $503,525

## Abstract

Project Summary
Chronic kidney disease (CKD) is estimated to affect over 14% of US adults and is increasing in prevalence
worldwide. The majority of cases are caused by glomerular diseases with sclerotic lesions, and transforming growth
factor β expression in podocytes is a common stress response signal associated with segmental sclerosis.
In the previous funding cycle we established a new hypothesis for “glomerular cell-cell crosstalk” using an
inducible transgenic mouse model (PodTbrI) that enables podocytes specific and ligand-independent
expression of transforming growth factor β type I receptor (TbrI) kinase. In this model, TbrI signaling in
podocytes results in the release of Edn1, followed by increased Ednra-mediated mitochondrial oxidative stress
and dysfunction of adjacent glomerular endothelial cells (GEC), which, in response, release factor(s) that
mediate damage and depletion of adjacent podocytes. This was also demonstrated in other models of
experimental podocytopathies (Balb/c + Adryamicin, PodDicerKO mice). We identified that a similar stressed
endothelial-to-podocyte crosstalk underlies segmental lesions in DKD. We characterized podocyte
mitochondrial dynamics in response to transforming growth factor β signaling. We also performed
transcriptomic analysis of isolated GECs after TbrI signaling activation and with this strategy we identified
novel GEC injury response pathways. Further, using state of the art proteomics, we identified a panel of novel
proteins released by stressed GECs that induce podocyte injury. We also identified key phenotypic markers of
cell crosstalk in vivo (GEC ultrastructural changes and loss of glomerular endothelial surface layer).
Our findings provide new insights into crosstalk of stressed GECs and podocytes in the pathogenesis of CKD.
We hypothesize that the identified GEC secreted proteins mediate podocyte injury and loss in CKD. In this
competitive renewal application, we aim to examine and validate the activity of the identified GEC-secreted
proteins and cell-cell crosstalk mechanisms mediating podocyte injury in CKD in the following 3 specific aims:
SPECIFIC AIMS: 1) To characterize GEC stress and the mechanisms leading to dysfunction and release of
crosstalk factors that impact podocytes. 2) To determine GEC response to podocyte activation in vivo. 3) To
characterize and validate podocyte responses to GEC secreted factors and determine their functional effects in
vitro with a novel 3-D kidney-on-a-chip microfluidic culture system and in vivo.
LONG-TERM: The studies proposed in this application will advance our understanding of communications
between cells in the glomerulus that underlie the initiation and progression of glomerular disease. The
significance of the proposed studies is in the discovery of the requirements and mechanisms for
interdependent crosstalk between activated podocytes and stressed endocapillary cells that determine
irreversible segmental sclerosis and disease progression. The...

## Key facts

- **NIH application ID:** 10228654
- **Project number:** 5R01DK097253-08
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Ilse Sofia Daehn
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $503,525
- **Award type:** 5
- **Project period:** 2013-04-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10228654

## Citation

> US National Institutes of Health, RePORTER application 10228654, Glomerular Cell-Cell Crosstalk and Injury (5R01DK097253-08). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10228654. Licensed CC0.

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