Dissertation
Examining CX3CR1 inhibition across murine models of tubulointerstitial disease
Doctor of Philosophy (Ph.D.), Drexel University
May 2026
DOI:
https://doi.org/10.17918/00011385
Abstract
Chronic kidney disease (CKD) is characterized by a progressive decline in renal function that frequently results in irreversible tubulointerstitial fibrosis. While the clinical etiology of CKD is diverse, in many cases, structural changes are heavily driven by a sustained, macrophage-mediated inflammatory response. The CX3CL1/CX3CR1 signaling axis is a recognized and critical mediator of this targeted immune cell recruitment. To target the inflammatory cascade, this research investigates the efficacy of AD-0145, a novel small-molecule competitive antagonist targeting the CX3CR1 receptor on infiltrating immune cells, across acute (folic acid), and chronic (oxalate and adenine) murine models of tubulointerstitial disease. Utilizing both prophylactic and delayed therapeutic dosing regimens, disease progression was tracked in vivo via transdermal glomerular filtration rate (GFR) devices, and inflammatory and fibrotic markers were recorded among others. In both acute and established disease states, systemic administration of AD-0145 successfully prevented the accumulation of F4/80+ macrophages. Crucially, flow cytometric analysis revealed that this receptor blockade significantly reduced both infiltrating and kidney resident macrophage populations. This reduction in renal macrophage burden significantly suppressed the secondary inflammatory cytokine cascade, halted downstream myofibroblast-associated markers, and limited interstitial Collagen III deposition, ultimately preserving renal function. Of major importance, this research also shows that inhibiting fractalkine's only known receptor, CX3CR1 reduces crystal presence in the oxalate model of CKD, a novel finding that has not been reported in the literature. Beyond evaluating pharmacological efficacy, critical assessment of these murine models revealed sex- and weight-dependent disparities in disease susceptibility. Ultimately, this research provides the first pre-clinical proof-of-concept for small-molecule CX3CR1 antagonism as a viable anti-inflammatory and anti-fibrotic therapy.
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Details
- Title
- Examining CX3CR1 inhibition across murine models of tubulointerstitial disease
- Creators
- Joshua Gale
- Contributors
- Maria Paula Martinez Cantarin (Advisor)Fred D. Allen, Jr. (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University
- Number of pages
- xvi, 130 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems (1997-2026); Drexel University
- Other Identifier
- 991022184775504721