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Abstract: SA-PO771

Activin A Is a Potential Mediator of TGFβ1-Induced Tubulointerstitial Fibrosis

Session Information

  • Hypertension and CVD: Mechanisms
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Hypertension and CVD

  • 1503 Hypertension and CVD: Mechanisms


  • Soomro, Asfia, McMaster University, Hamilton, Ontario, Canada
  • Li, Renzhong, McMaster University, Hamilton, Ontario, Canada
  • Zhang, Dan, McMaster University, Hamilton, Ontario, Canada
  • O'Neil, Kian S., McMaster University, Hamilton, Ontario, Canada
  • Macdonald, Melissa, McMaster University, Hamilton, Ontario, Canada
  • Gao, Bo, McMaster University, Hamilton, Ontario, Canada
  • Krepinsky, Joan C., McMaster University, Hamilton, Ontario, Canada

Chronic kidney disease (CKD) is a rising health issue in North America, characterized by progressive renal fibrosis often leading to organ failure. TGFβ1 is a central mediator of fibrosis in CKD of diverse etiology, but its direct inhibition is limited by adverse effects. We recently showed in glomerular mesangial cells (MC) that activin A (ActA) mediates TGFβ1 profibrotic effects through regulation of both canonical Smad3 and noncanonical MRTF-A signaling. Here we study the potential role of ActA in the development of tubulointerstitial fibrosis (TIF), a major determinant of kidney function decline in CKD. We further assess the promoter regulation of ActA by TGFβ1.


Renal fibrosis was induced in mice overexpressing (OE) TGFβ1 using 2 models: 5/6 nephrectomy (Nx) and unilateral ureteral obstruction (UUO). UUO mice were treated with a neutralizing ActA antibody to assess effects on fibrosis. Primary mouse MC, human renal proximal tubular epithelial cells (PTEC, HK2) and rat renal fibroblasts (RF) were used. ActA and Activin B (ActB) were inhibited with a neutralizing antibody or follistatin. Transcriptional activity of the ActA promoter was studied using a luciferase reporter plasmid and a series of deletion constructs.


TGFβ1 OE augmented fibrosis and activin levels in Nx and UUO. ActA neutralization inhibited Smad3 activation and fibrosis after UUO in wild-type and TGFβ1 OE mice. In both models, ActA and B were significantly increased in tubular cells, which largely colocalized to PTEC identified by megalin. We thus studied the potential role of activins in tubular-fibroblast crosstalk. TGFβ1 increased secretion of ActA and B from HK2 cells, with a greater ActA effect. Media from HK2 treated with TGFβ1 induced RF Smad3 activation and fibrotic responses (matrix synthesis, αSMA induction). These were blocked by follistatin or ActA, but not ActB, neutralization. In MC, we found the -350bp region of the ActA promoter is required for TGFβ1 regulation. Interestingly, a novel CT microsatellite site upstream of this which suppressed promoter activity was also identified.


ActA is induced by TGFβ1 and mediates its profibrotic effects, with relevance to both glomerular and TIF. Its inhibition is being evaluated as a novel treatment for fibrosis in CKD.