# Antifibrotic Actions of SARA

> **NIH NIH R01** · LURIE CHILDREN'S HOSPITAL OF CHICAGO · 2020 · $291,360

## Abstract

Fibrogenesis plays a major role in chronic kidney disease (CKD) progression. Our laboratory has
identified Smad anchor for receptor activation (SARA) as a candidate anti-fibrotic molecule. Originally
described as a TGF-β receptor adaptor molecule that facilitates Smad signaling, SARA has a broader
role as a scaffolding protein that assembles molecules in complexes to direct cell signaling events. We
have shown how SARA participates in endosomal signaling, and that its expression helps to maintain
cells in a differentiated state. SARA is downregulated in cells that are subjected to fibrogenic stimuli,
concomitant with the cells presenting a fibrogenic phenotype. Overexpressing SARA in these cells
prevents the phenotypic switch associated with fibrosis; conversely, knocking down SARA amplifies
collagen production in response to TGF-β. In preliminary studies, we show: 1) SARA expression is
markedly reduced in kidneys undergoing fibrosis, 2) aristolochic acid-induced tubulointerstitial fibrosis is
reduced in mice that overexpress SARA in an inducible fashion, and 3) overexpressed SARA prevents
fibrosis in a Drosophila larval heart-kidney tube model where fibrogenesis is induced by knockdown of
histone-modifying genes. Together, these data support the hypothesis that SARA maintains cells in
a fibrosis-resistant state. By regulating the expression of SARA and/or molecules that mediate
SARA actions, we can modify the events leading to renal fibrosis. Here, we propose three specific
aims to test our hypothesis and will determine: (1) How SARA expression changes during renal fibrosis
in mice, and if increasing or blocking SARA expression using transgenic approaches ameliorates or
accelerates disease, respectively. (2) How SARA expression is regulated during fibrosis in vitro and in
vivo. We have found that the transcriptional repressor, BHLHE40, inhibits SARA expression; and the
anti-fibrotic protein, soluble Klotho, stimulates SARA expression. We will determine how these
molecules act through SARA to influence the outcome of fibrotic renal disease. (3) How SARA signals
downstream to protect cells from the fibrogenic `switch.' We will examine how SARA affects Wnt/β-
catenin signaling and seek new effector mechanisms of SARA through RNA-Seq of TGF-β-treated
mouse cells, and of Drosophila larvae undergoing pericardial nephrocyte-associated fibrosis.
 SIGNIFICANCE: Completion of these studies will elucidate the mechanism by which SARA
modulates cellular fibrogenic activity, with a goal of identifying novel therapeutic targets to prevent or
slow CKD-associated fibrosis.

## Key facts

- **NIH application ID:** 10020394
- **Project number:** 5R01DK105055-05
- **Recipient organization:** LURIE CHILDREN'S HOSPITAL OF CHICAGO
- **Principal Investigator:** Tomoko Hayashida
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $291,360
- **Award type:** 5
- **Project period:** 2017-08-24 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10020394

## Citation

> US National Institutes of Health, RePORTER application 10020394, Antifibrotic Actions of SARA (5R01DK105055-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10020394. Licensed CC0.

---

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