Abstract: TH-PO0891
Investigating Hepatocyte Nuclear Factor 4 Alpha as a Central Regulator of Kidney Graft Repair
Session Information
- Transplantation: Basic Research
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Transplantation
- 2101 Transplantation: Basic
Authors
- Neupane, Slaghaniya, University of Toronto, Toronto, Ontario, Canada
- Petrovic, Stefan, University Health Network, Toronto, Ontario, Canada
- Saha, Aninda Dibya, Stanford University, Stanford, California, United States
- Allen, Maya A., University of Toronto, Toronto, Ontario, Canada
- Sachewsky, Nadia, University Health Network, Toronto, Ontario, Canada
- Selzner, Markus, University Health Network, Toronto, Ontario, Canada
- Robinson, Lisa, University of Toronto, Toronto, Ontario, Canada
- Clotet Freixas, Sergi, McMaster University, Hamilton, Ontario, Canada
- Konvalinka, Ana, University of Toronto, Toronto, Ontario, Canada
Background
Kidney transplantation is the best treatment for end-stage kidney disease, but ischemia-reperfusion injury (IRI) harms all grafts. Previously, we showed better kidney function after IRI is tied to preserved expression of mitochondrial proteins in normothermic ex vivo kidney perfusion. We identified a regulator of these mitochondrial proteins, hepatocyte nuclear factor 4a (HNF4A), which may be a novel target for kidney repair. Our goal is to test if an HNF4A agonist, N-trans caffeoyltyramine (NCT), protects against IRI.
Methods
We will evaluate NCT treatment in male and female primary proximal tubular cells (PTECs), and in male and female mice subjected to bilateral IRI. First, we inhibited HNF4A in primary PTECs, and then assessed gene expression, cell death and mitochondrial function. Lastly, kidney function and stucture of mice subjected to bilateral IRI were assessed on post operative day 2 and 14.
Results
HNF4A inhibition in vitro increased PTEC death and decreased mitochondrial function. We developed a sex-specific model of bilateral IRI and demonstrated that warm ischemia (21-min males and 28-min females) impairs kidney function on post-operative day 2, indicated by elevated serum creatinine. Mice also developed tubulointerstitial fibrosis on post-operative day 14. Gene expression of Hnf4a and its targets (Cpt2, Etfb) and interactors (Ppargc1a, Ppara) all decreased on post operative day 2 and remained decreased on post operative day 14 in males.
Conclusion
Based on the preliminary results, HNF4A is important for the metabolic function and viability of PTECs. If NCT reduces IRI by preserving mitochondrial function, it could be administered prior to transplantation to improve graft outcomes.