# Mechanisms and Treatment of Kidney Fibrosis

> **NIH VA I01** · ST. LOUIS VA MEDICAL CENTER · 2020 · —

## Abstract

Project Summary
 Chronic kidney disease (CKD) affects ~15% of the U.S. population. Although a broad range of insults
initiate kidney injury, fibrosis is a hallmark of all forms of progressive CKD. In spite of advances in delineating
pathways that contribute to kidney fibrosis, there are no specific treatments for this serious disorder.
 TGF-β signaling is a central mediator of fibrosis in multiple tissues making it an attractive therapeutic target.
However, because these cytokines have a wide range of roles in human physiology and pathology, the
challenge has been to find a therapeutic strategy that is selective for the diseased target tissue to improve
efficacy and safety profiles. A promising approach is to disrupt TGF-β activation in the injured tissue. TGF-β is
secreted as a latent, inactive complex that is sequestered in high concentrations in the extracellular matrix. A
critical step in the regulation of TGF-β signaling is activation of the latent complex by binding of alpha v (αv)
integrins to lysine-glycine-aspartic acid (RGD) motifs. In Aim 1 of this proposal, we will determine if a novel
small molecule RGD peptidomimetic inhibitor of TGF-β activation will reduce kidney fibrosis in mouse models
of nephrotoxicity, ischemia and urinary tract obstruction. Our preliminary studies indicated that this compound
is safe and effective and thus a highly promising candidate for future translational studies in patients.
 Developing effective treatments for kidney disease requires increased knowledge about molecular
mechanisms that drive progressive fibrosis of the organ. Myofibroblasts, derived from peri-vascular
mesenchymal progenitor cells are the principal source of extracellular matrix deposition in organ fibrosis.
However, the cellular and molecular pathways that control the formation of these cells in response to injury are
not well understood. In Aim 2, we will investigate the molecular mechanisms by which alpha v (αv) integrins
regulate the proliferation and differentiation of myofibroblasts after injury.
 These pre-clinical studies will advance knowledge about mechanisms of organ fibrosis and have the
potential to identify a novel therapeutic strategy to treat chronic kidney disease in veterans.

## Key facts

- **NIH application ID:** 9863992
- **Project number:** 5I01BX003674-03
- **Recipient organization:** ST. LOUIS VA MEDICAL CENTER
- **Principal Investigator:** MICHAEL I RAUCHMAN
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9863992

## Citation

> US National Institutes of Health, RePORTER application 9863992, Mechanisms and Treatment of Kidney Fibrosis (5I01BX003674-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9863992. Licensed CC0.

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