# Molecular Mechanisms of Kidney Fibrosis

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2024 · —

## Abstract

Acute kidney injury (AKI) predisposes to chronic kidney disease (CKD) which often progresses to organ failure.
One of the hallmarks of CKD is tubulointerstitial fibrosis characterized by extracellular matrix accumulation,
tubular atrophy and inflammatory cell infiltration. The main cells targeted by AKI are proximal tubule epithelial
cells (PTECs) that contribute to CKD by producing pro-inflammatory cytokines and extracellular matrix and by
stimulating myofibroblast differentiation of surrounding fibroblasts, leading to interstitial fibrosis. The goal of this
grant is to investigate the molecular mechanisms whereby PTECs control pro-inflammatory and pro-fibrotic
signaling in order to devise more effective therapies to halt and prevent AKI and its progression to CKD. Although
many pathways have been implicated in both initiation and progression to kidney fibrosis, we will focus on
Recepteur d'Origine Nantai (RON) and transforming growth factor beta (TGF-β) receptor II (TβRII).
Based on the evidence that TβRII contains 5 phosphorylatable tyrosines and some of these tyrosines control
activation of TβRII-mediated profibrotic signaling, we started to investigate the mechanisms whereby tyrosine
phosphorylation of TβRII is controlled. We identified RON as a major receptor tyrosine kinase able to
phosphorylate the cytoplasmic domain of TβRII. We show that RON and TβRII are expressed on PTECs and
RON activation leads to TβRII tyrosine phosphorylation and enhances TβRII-mediated pro-inflammatory (e.g.
IL-18 secretion) and pro-fibrotic (e.g. SMAD3 activation) signaling. In addition, we show that treatment of PTECs
with the RON ligand MST1 leads to tyrosine phosphorylation of pro-fibrotic STAT3 and secretion of TGF-β, a
key determinant in myofibroblast differentiation and development of tubulointerstitial fibrosis. Importantly, mice
treated with the RON inhibitor Crizotinib show reduced AKI-induced proximal tubule injury characterized by
decreased levels of tyrosine phosphorylated RON and TβRII, macrophage infiltration, SMAD3 and STAT3
activation, and collagen production. Based on these results and the finding that increased tyrosine
phosphorylation of RON and TβRII is detected in the kidneys of mice subjected to severe AKI that progresses
to CKD, we propose that RON in PTECs contributes to kidney injury and fibrosis by promoting 1) tyrosine
phosphorylation of TβRII thus enhancing TβRII-mediated production of pro-inflammatory cytokines (IL-18) and
activation of pro-fibrotic molecules (SMAD3); and 2) TGF-β secretion in a STAT3 dependent manner thus
inducing myofibroblast differentiation. The aims of this grant are designed to define the contribution of
RON/STAT3 and RON/TβRII axes in kidney disease and to determine if their inhibition is beneficial in
slowing/halting AKI and its progression to CKD.
In Aim 1 we will study the role of RON-mediated phosphorylation of TβRII in AKI and AKI-to-CKD progression
using a genetic and pharmacological approach. We will in...

## Key facts

- **NIH application ID:** 10721354
- **Project number:** 5I01BX002025-10
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** AMBRA POZZI
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2013-04-01 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10721354

## Citation

> US National Institutes of Health, RePORTER application 10721354, Molecular Mechanisms of Kidney Fibrosis (5I01BX002025-10). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10721354. Licensed CC0.

---

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