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Unilateral Ureteral Obstruction Model for Investigating Kidney Interstitial Fibrosis
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Targeting AXL cellular networks in kidney fibrosis
Sturla M Grøndal1, Magnus Blø2, Linn I H Nilsson2
1Department of Biomedicine, University of Bergen, Bergen, Norway.
Frontiers in Immunology
|November 19, 2024
Summary
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.
