Antifibrotic Actions of SARA

Project: Research project

Project Details

Description

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.
StatusActive
Effective start/end date6/2/196/30/21

Funding

  • Ann & Robert H. Lurie Children's Hospital of Chicago (A19-0185-S001-NU//5R01DK105055-04)
  • National Institute of Diabetes, Digestive and Kidney Diseases (A19-0185-S001-NU//5R01DK105055-04)

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