Abstract: PUB579
Dose-Dependent Nephroprotective Effects of an ALK5 Inhibitor in the Unilateral Ureteral Obstruction (UUO) Mouse Model of Kidney Fibrosis
Session Information
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Jensen, Ditte Marie, Gubra, Hørsholm, Denmark
- Frias Hernandez, Alex, Gubra, Hørsholm, Denmark
- Ougaard, Maria Katarina, Gubra, Hørsholm, Denmark
- Christensen, Michael, Gubra, Hørsholm, Denmark
- Sembach, Frederikke Emilie, Gubra, Hørsholm, Denmark
Background
Development of renal fibrosis is a hallmark of chronic kidney disease (CKD) and an essential factor for progressive loss of kidney function and development of end-stage kidney disease. The unilateral ureteral obstruction (UUO) mouse is a widely used surgery-induced model of CKD with rapid induction of renal inflammation and fibrosis. Here, we characterized the effect of an anti-fibrotic TGF-β type 1 receptor kinase inhibitor (ALK5 inhibitor, ALK5i) on renal outcomes in the UUO mouse.
Methods
Male C57BL/6J mice (9 weeks old) were randomised into study groups based on body weight and were either sham-operated or underwent UUO surgery. UUO mice received vehicle or ALK5i (3, 10 or 30 mg/kg, PO, BID) for 8 days. Vehicle-dosed sham-operated mice served as controls. At termination, both kidneys were weighed, and the obstructed left kidney was processed kidney hydroxy proline (HP) and for quantitative histological assessment of macrophage infiltration (F4/80), fibrosis (Col1a1, Col3a1), myofibroblast activation (α-SMA) and tubular injury (KIM-1). Plasma was sampled for measurement of KIM-1 levels.
Results
UUO mice displayed marked kidney tubular injury, macrophage infiltration, myofibroblast activation, and fibrosis as compared to sham-operated animals. ALK5i dose-dependently improved kidney histology, plasma KIM-1 levels, and kidney HP (0.148 vs 0.214 µg/mg).
Conclusion
ALK5i exerted dose-dependent nephroprotective effects in the UUO mouse. Given the rapid induction of fibrosis and inflammation, the UUO mouse is optimal for screening of compounds with potential anti-inflammatory and anti-fibrotic effects.
Funding
- Commercial Support – Gubra