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Updated: Jun 7, 2025
Unilateral Ureteral Obstruction Model for Investigating Kidney Interstitial Fibrosis
Published on: April 25, 2025
Targeting AXL cellular networks in kidney fibrosis
Sturla M Grøndal1, Magnus Blø2, Linn I H Nilsson2
1Department of Biomedicine, University of Bergen, Bergen, Norway.
Introduction:
The incidence of chronic kidney disease (CKD) is increasing, in parallel with risk factors including obesity and diabetes mellitus. AXL plays a central role in CKD, providing a rationale to evaluate clinical AXL targeting agents.
Methods:
To determine the efficacy and underlying molecular mechanisms of AXL inhibition in CKD, we employed a murine unilateral ureteral obstruction (UUO) model preventively treated with a selective AXL kinase inhibitor (bemcentinib) during disease progression. We isolated kidneys at an early (3 days) or late (15 days) timepoint and profiled the cell populations using mass cytometry.
Results:
Preventive treatment with bemcentinib significantly attenuated fibrosis in the UUO model. The anti-fibrotic effect correlated with a decrease in mesangial cells and inhibition of innate immune cell infiltration, while the proportion of epithelial cells increased. We mapped AXL expression to a unique network of cells in the kidney: mesangial cells, pericytes, macrophages and dendritic cells.
Discussion:
We propose that AXL targeting affects an important cellular interaction network underlying fibrotic progression. These results support the clinical application of AXL targeting agents to treat CKD.
Insights
Targeting AXL kinase with bemcentinib reduced kidney fibrosis in a mouse model. This approach inhibited immune cell infiltration and mesangial cell proliferation, supporting AXL inhibitors for chronic kidney disease (CKD) treatment.
Area of Science:
- Nephrology
- Molecular Biology
- Oncology
Background:
- Chronic kidney disease (CKD) incidence is rising globally, linked to obesity and diabetes.
- AXL receptor tyrosine kinase is implicated in CKD pathogenesis, making it a therapeutic target.
Purpose of the Study:
- To investigate the efficacy of AXL inhibition in mitigating kidney fibrosis.
- To elucidate the molecular mechanisms of AXL inhibition in a preclinical CKD model.
Main Methods:
- Utilized a murine unilateral ureteral obstruction (UUO) model of kidney injury.
- Administered bemcentinib, a selective AXL kinase inhibitor, preventively during disease progression.
- Analyzed kidney tissue at early and late timepoints using mass cytometry to profile cell populations.
Main Results:
- Preventive bemcentinib treatment significantly attenuated renal fibrosis in the UUO model.
- AXL inhibition decreased mesangial cell counts and innate immune cell infiltration.
- Increased proportion of epithelial cells observed in AXL-inhibited kidneys.
- AXL expression was identified in mesangial cells, pericytes, macrophages, and dendritic cells.
Conclusions:
- AXL targeting disrupts a key cellular network driving fibrotic progression in CKD.
- These findings provide a strong rationale for the clinical development of AXL inhibitors for treating CKD.
