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Published on: November 10, 2021
A therapeutic target for CKD: activin A facilitates TGFβ1 profibrotic signaling
Asfia Soomro1, Mohammad Khajehei1, Renzhong Li1
1Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Canada.
Background:
TGFβ1 is a major profibrotic mediator in chronic kidney disease (CKD). Its direct inhibition, however, is limited by adverse effects. Inhibition of activins, also members of the TGFβ superfamily, blocks TGFβ1 profibrotic effects, but the mechanism underlying this and the specific activin(s) involved are unknown.
Methods:
Cells were treated with TGFβ1 or activins A/B. Activins were inhibited generally with follistatin, or specifically with neutralizing antibodies or type I receptor downregulation. Cytokine levels, signaling and profibrotic responses were assessed with ELISA, immunofluorescence, immunoblotting and promoter luciferase reporters. Wild-type or TGFβ1-overexpressing mice with unilateral ureteral obstruction (UUO) were treated with an activin A neutralizing antibody.
Results:
In primary mesangial cells, TGFβ1 induces secretion primarily of activin A, which enables longer-term profibrotic effects by enhancing Smad3 phosphorylation and transcriptional activity. This results from lack of cell refractoriness to activin A, unlike that for TGFβ1, and promotion of TGFβ type II receptor expression. Activin A also supports transcription through regulating non-canonical MRTF-A activation. TGFβ1 additionally induces secretion of activin A, but not B, from tubular cells, and activin A neutralization prevents the TGFβ1 profibrotic response in renal fibroblasts. Fibrosis induced by UUO is inhibited by activin A neutralization in wild-type mice. Worsened fibrosis in TGFβ1-overexpressing mice is associated with increased renal activin A expression and is inhibited to wild-type levels with activin A neutralization.
Conclusions:
Activin A facilitates TGFβ1 profibrotic effects through regulation of both canonical (Smad3) and non-canonical (MRTF-A) signaling, suggesting it may be a novel therapeutic target for preventing fibrosis in CKD.
Insights
Activin A enhances kidney fibrosis by promoting TGFβ1 effects through Smad3 and MRTF-A signaling. Neutralizing activin A reduces fibrosis in mouse models, indicating its potential as a therapeutic target for chronic kidney disease.
Area of Science:
- Nephrology
- Cell Biology
- Molecular Biology
Background:
- Transforming growth factor-beta 1 (TGFβ1) is a key driver of fibrosis in chronic kidney disease (CKD).
- Direct TGFβ1 inhibition is limited by side effects.
- Activins, part of the TGFβ superfamily, can block TGFβ1's profibrotic actions, but the precise mechanisms and involved activins remain unclear.
Purpose of the Study:
- To elucidate the mechanism by which activins mediate TGFβ1-induced profibrotic effects in CKD.
- To identify the specific activin(s) responsible for these effects.
- To evaluate activin A as a potential therapeutic target for CKD fibrosis.
Main Methods:
- Primary mesangial and tubular cells were treated with TGFβ1 or activins A/B.
- Activin activity was modulated using follistatin, neutralizing antibodies, or receptor downregulation.
- Signaling pathways (Smad3, MRTF-A) and profibrotic responses were assessed using molecular and cellular assays.
- In vivo studies involved unilateral ureteral obstruction (UUO) models in wild-type and TGFβ1-overexpressing mice treated with an activin A neutralizing antibody.
Main Results:
- TGFβ1 stimulated primary mesangial cells to secrete activin A, which prolonged profibrotic responses by enhancing Smad3 phosphorylation and promoting TGFβ type II receptor expression.
- Activin A also activated non-canonical MRTF-A signaling, contributing to TGFβ1-induced transcription.
- TGFβ1 induced activin A secretion from tubular cells, and blocking activin A inhibited TGFβ1's profibrotic effects in renal fibroblasts.
- Activin A neutralization attenuated fibrosis in wild-type mice undergoing UUO and reduced exacerbated fibrosis in TGFβ1-overexpressing mice.
Conclusions:
- Activin A plays a crucial role in facilitating TGFβ1-driven fibrosis in CKD by modulating both canonical Smad3 and non-canonical MRTF-A signaling pathways.
- These findings highlight activin A as a significant mediator of kidney fibrosis.
- Activin A represents a promising novel therapeutic target for the treatment of fibrosis in chronic kidney disease.
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