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ORIGINAL RESEARCH article

Front. Mol. Biosci.

Sec. Cellular Biochemistry

Volume 12 - 2025 | doi: 10.3389/fmolb.2025.1607043

This article is part of the Research TopicInnovative Therapeutic Strategies for Chronic Kidney Disease: From Molecular Mechanisms to Clinical PracticeView all 6 articles

Analysis of TGFβ1-Induced Activin A Gene Expression in Kidney Mesangial Cells

Provisionally accepted
Asfia  SoomroAsfia SoomroKennedy  NmechaKennedy NmechaJackie  TrinkJackie TrinkRenzhong  LiRenzhong LiJoan  KrepinskyJoan Krepinsky*
  • McMaster University, Hamilton, Canada

The final, formatted version of the article will be published soon.

Abstract Introduction: The cytokine activin A is emerging as an important regulator of kidney fibrosis. Its expression, negligible in normal kidney, is significantly increased in various fibrotic kidney diseases. TGFβ1 is a cytokine belonging to the same family, which is well established to be a central mediator of kidney fibrosis. Although targeting TGFβ1 therapeutically is not feasible due to its homeostatic roles, we previously showed that activin A is upregulated by, and mediates the profibrotic effects of, TGFβ1. Methods: We investigated the transcriptional regulation of activin A by TGFβ1 in primary kidney mesangial cells (MC). Cells were transfected with a luciferase reporter construct containing the activin A promoter or a series of deletion constructs. Guided by MatInspector, key TGFβ1-responsive consensus elements were identified. Results: TGFβ1 increased transcription of the activin A subunit inhba. Using a series of deletion constructs of the inhba promoter, we identified a critical regulatory region located 350bp from the transcription start site that is responsive to TGFβ1. Analysis of this region for transcription factor regulatory elements, coupled with mutation analyses and transcription factor downregulation with siRNA, showed that Stat5 and FoxP1, but not Sox9, regulate inhba transcription by TGFβ1. Interestingly, although no consensus binding site in this region was identified for Smad3, a well-established mediator of TGFβ1 signaling, both a Smad3 inhibitor and use of MC isolated from Smad3 knockout kidneys, showed its requirement for the TGFβ1 response. We further identified a CT microsatellite just upstream of 350bp which suppressed promoter activity. Conclusions: These findings provide insight into potential therapeutic targets for activin A targeting and attenuation of kidney fibrosis.

Keywords: activin A, TGFβ1, kidney fibrosis, promoter activity, Regulatory elements

Received: 07 Apr 2025; Accepted: 04 Sep 2025.

Copyright: © 2025 Soomro, Nmecha, Trink, Li and Krepinsky. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Joan Krepinsky, McMaster University, Hamilton, Canada

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