Abstract: FR-PO1049
Dose-Dependent Nephroprotective Effects of an ALK5 Inhibitor in the Unilateral Ureteral Obstruction (UUO) Mouse Model of Kidney Fibrosis
Session Information
- CKD Mechanisms: Progression, Fibrosis, and Beyond
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Bak, Stine Thorhauge, Gubra, Hoersholm, Denmark
- Nøhr-Meldgaard, Jacob, Gubra, Hoersholm, Denmark
- Jensen, Ditte Marie, Gubra, Hoersholm, Denmark
- Rune, Ida, Gubra, Hoersholm, Denmark
- Sembach, Frederikke Emilie, Gubra, Hoersholm, Denmark
- Frias Hernandez, Alex, Gubra, Hoersholm, Denmark
- Secher, Thomas, Gubra, Hoersholm, Denmark
- Ougaard, Maria Katarina, Gubra, Hoersholm, Denmark
- Christensen, Michael, Gubra, Hoersholm, 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 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 and plasma KIM-1 levels.
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