A therapeutic target for CKD: activin A facilitates TGFβ1 profibrotic signaling

Abstract

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.

Circulating Activin A, Kidney Fibrosis, and Adverse Events

“…Activin A promotes fibroblast differentiation and extracellular matrix production, suggesting it as a target to combat kidney fibrosis. 26 In our data, exogenous activin A promoted fibroblast activation, while Inhba knockdown attenuated TGF- β –induced fibroblast activation, implying a regulatory role for activin A. However, exogenous activin A was unable to reverse the effects of Inhba knockdown, highlighting differences between exogenous and endogenous activin A in influencing fibroblast activation.…”

“…Some researchers report increased expression in tubular epithelium, while others identify myofibroblasts as the primary source in damaged kidneys. 16,19,26,27 In this study, we assessed plasma and kidney activin A levels and their correlation with kidney fibrosis severity and disease outcome in 339 participants with biopsy-proven kidney diseases. In vitro experiments explored the potential involvement of activin A in fibroblast activation and kidney fibrosis.…”

MYH1G-AS is a chromatin-associated lncRNA that regulates skeletal muscle development in chicken

“…It is well established that the TGF-β signaling pathway is widely involved in the regulation of cell growth, differentiation, and development [ 37 – 39 ]. As a family of signal transduction molecules, the SMAD family plays important roles in mediating the TGF-β signaling pathway [ 40 – 42 ].…”

Curriculum vitae of CUG binding protein 1 (CELF1) in homeostasis and diseases: a systematic review

“…Chronic kidney disease (CKD) represents a significant health risk, and renal fibrosis is a key factor in the progression of CKD [ 46 , 47 ]. The excessive activation of fibroblasts is a crucial initiating event in the development of renal fibrosis, which poses challenges for effective therapeutic interventions.…”