Abstract: FR-PO115
Follistatin as a Novel Therapeutic Agent in CKD
Session Information
- Molecular Mechanisms of CKD - II
October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 1903 CKD (Non-Dialysis): Mechanisms
Authors
- Mehta, Neel, McMaster University, Hamilton, Ontario, Canada
- Zhang, Dan, St. Joseph's Hospital, Hamilton, Ontario, Canada
- Van krieken, Richard, McMaster University, Hamilton, Ontario, Canada
- He, Juehua, McMaster University, Hamilton, Ontario, Canada
- Gao, Bo, St. Joseph's Hospital, Hamilton, Ontario, Canada
- Krepinsky, Joan C., McMaster University, Hamilton, Ontario, Canada
Background
Chronic kidney disease (CKD), characterized by progressively worsening glomerular and interstitial fibrosis accompanied by declining kidney function, is a major cause of morbidity and mortality. Follistatin (FST) is a glycoprotein which neutralizes members of the TGFβ superfamily, most prominently the activins. It does not directly inhibit TGFβ1. Recent studies have shown an increase in activin A in serum of mice with CKD. Here we assess the therapeutic efficacy of FST in a mouse model of CKD with reduced renal mass and proteinuria.
Methods
Male CD1 mice underwent either a 5/6 nephrectomy or sham surgery, after which 5μg human recombinant FST (PB01, Paranta Biosciences Ltd) or vehicle was given intraperitoneally every other day for 9 weeks. At endpoint, blood pressure, renal function, albuminuria and renal pathology were assessed.
Results
Activin A was significantly upregulated in the serum and kidneys of mice with CKD. Activation of Smad3, a downstream mediator of activin A signaling, was increased in CKD kidneys. This was inhibited by FST. Mice with CKD had elevated blood pressure, a significantly diminished glomerular filtration rate (GFR) and severe albuminuria. Pathologically, mice with CKD had prominent glomerulosclerosis and tubulointerstitial fibrosis, assessed using trichrome and picrosirius red staining. Immunoblotting showed increases in the profibrotic cytokine CTGF and the matrix proteins fibronectin, collagen Iα1 and collagen 4α1. Clinically, FST improved blood pressure, GFR and albuminuria, and pathologically both glomerulosclerosis and tubulointerstitial fibrosis were significantly attenuated.
Conclusion
Our data support a prominent pathologic role for the TGFβ family member activin A in CKD. We show that administration of the activin neutralizing protein FST is effective in preserving kidney structure and function and in attenuating the progression of CKD. These data highlight the promising role of FST as a novel renoprotective agent in CKD.
Funding
- Government Support - Non-U.S.