# Matrix receptors in chronic kidney disease

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $339,433

## Abstract

Chronic kidney disease (CKD) is a progressive loss of kidney function leading to kidney failure. Despite
treatment of CKD with renoprotective agents, there is no therapy that slows or halts disease progression.
Hallmarks of CKD are tubulointerstitial (TI) fibrosis, tubular atrophy, and inflammatory cell infiltration. Proximal
tubules cells contribute to TI fibrosis and to the pathogenesis of CKD by promoting pro-inflammatory cytokines
and extracellular matrix production, as well as myofibroblast differentiation of surrounding fibroblasts.
The discoidin domain receptor 1 (DDR1) is a matrix receptor that is activated by collagen, upregulated in
proximal tubules of injured kidneys and a positive regulator of collagen synthesis. Moreover, DDR1 induces the
secretion of inflammatory cytokines and TGF-β that induces myofibroblast differentiation. Using a mouse
model of severe acute kidney injury (AKI) that progresses to CKD, we showed that DDR1KO mice have
reduced acute tubular injury and long-term post injury fibrosis. This protection is accompanied by decreased
proximal tubule damage, macrophage infiltration, deposition of TI collagen, and αSMA positive cells. In
proximal tubule cells, DDR1 promotes synthesis of collagen, activation of pro-fibrotic intracellular signaling, and
secretion of pro-inflammatory cytokines and TGF-β. Thus, DDR1 plays a deleterious role in the development of
TI fibrosis making it a promising therapeutic target. Based on these findings, we hypothesize that upregulation
of DDR1 on proximal tubule cells contributes to TI fibrosis by activating pro-fibrotic pathways and
promoting secretion of pro-inflammatory and pro-fibrotic cytokines.
Aim 1 will determine the contribution of DDR1 on proximal tubule cells to TI fibrosis. We hypothesize that
DDR1 is a critical modulator of TI fibrosis that regulates pro-fibrotic and pro-inflammatory signaling in proximal
tubule cells. We will induce severe AKI that progresses to CKD in DD1KO mice and newly generated TSH-
DDR1 transgenic mice in which the TetO7-CMV promoter drives expression of a DDR1 shRNA capable of
inhibiting DDR1 expression in the presence of a cell specific reverse tetracycline transactivator. To confirm that
DDR1 contributes to TI fibrosis, we will treat mice with selective DDR1 inhibitors and follow injury over time.
Aim 2 will determine the mechanisms whereby DDR1 contributes to TI fibrosis. Based on evidence that DDR1
promotes the phosphorylation of pro-fibrotic and pro-inflammatory transcription factors (canonical signaling)
and it translocates to the nucleus where it interacts with chromatin and the RNA polymerase subunit RBP6, we
will perform in vitro studies to test the hypothesis that DDR1 regulates gene transcription by activating
canonical intracellular signaling as well as by acting as a transcription co-factor.
This study will 1) generate novel insights into the molecular basis whereby DDR1 contributes to TI fibrosis and
CKD; and 2) assess whether inhibition of D...

## Key facts

- **NIH application ID:** 10217119
- **Project number:** 5R01DK119212-04
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Corina Marilena Borza
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $339,433
- **Award type:** 5
- **Project period:** 2018-09-25 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10217119

## Citation

> US National Institutes of Health, RePORTER application 10217119, Matrix receptors in chronic kidney disease (5R01DK119212-04). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/10217119. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*