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Kidney Week

Abstract: SA-OR072

A New Therapeutic Target for CKD: Activins Facilitate TGF-β1 Profibrotic Signaling in Kidney Mesangial Cells

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Soomro, Asfia, McMaster University, Hamilton, Ontario, Canada
  • Mehta, Neel, McMaster University, Hamilton, Ontario, Canada
  • Gao, Bo, St. Joseph's Hospital, Hamilton, Ontario, Canada
  • Krepinsky, Joan C., McMaster University, St. Joseph's Hospital, Hamilton, Ontario, Canada
Background

Chronic kidney disease (CKD) is a rising health issue for approximately 11% of the North American population and is characterized by progressive renal fibrosis and loss of kidney function leading to end-stage renal disease requiring dialysis or transplantation. The profibrotic cytokine TGFβ1 is a central mediator of kidney fibrosis in CKD; blocking it is not feasible due to adverse effects thereby requiring alternate therapeutic approaches. We have shown that TGFβ1 requires activins, a TGFβ superfamily member, for its profibrotic effects. However, since they both signal via the same canonical Smad pathway, how activins enable TGFβ1-induced fibrosis is not known and was investigated here.

Methods

Primary mouse mesangial cells were used. Activin A (AA) and B (AB) were inhibited with a neutralizing antibody, follistatin or siRNA to their receptor, ALK4. Smad3 transcriptional activity was assessed using a CAGA12 luciferase reporter.

Results

TGFβ1 induced strong early activation (60min) of Smad3, while AA/AB caused later activation (48h). TGFβ1 also induced the secretion of AA, with minimal effect on AB. Inhibition of AA, but not AB, decreased TGFβ1-induced Smad3 activation, assessed by phosphorylation and nuclear accumulation, and its transcriptional activity. This demonstrated a requirement for AA for canonical Smad3 signaling by TGFβ1. However, activin inhibition also decreased TGFβ1-induced activation of the α-smooth muscle actin (SMA) promoter more effectively than Smad3 transcriptional activity. Since SMA is a well-known Smad3-mediated TGFβ1 target which also requires non-canonical signaling, these data suggest that AA adds to TGFβ1 signaling activation via a non-canonical pathway. The transcription factors YAP/TAZ are known Smad3 comediators of SMA. Interestingly, activin inhibition prevented TGFβ1-induced YAP, but not TAZ, activation and upregulation. Finally, we confirmed that TGFβ1-induced expression of the extracellular matrix proteins fibronectin and collagen IV were prevented by activin inhibition in mesangial cells. Future experiments will investigate the relevance of Activin-induced TGFβ1 profibrotic signalling in a mouse model of CKD.

Conclusion

AA facilitates TGFβ1 profibrotic effects through regulation of both canonical and non-canonical signaling. Thus, targeting AA represents a novel antifibrotic treatment approach for CKD.

Funding

  • Other NIH Support