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Abstract: FR-PO1062

Treatment of Glomerulonephritis Using Drugs Targeting Folate Receptor Expressing Activated Macrophages

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Garcia, Gabriela E., University of Colorado Denver, Greenwood Village, Colorado, United States
  • Lu, Yingjuan June, Endocyte, West Lafayette, Indiana, United States
  • Truong, Luan D., The Methodist Hospital , Houston, Texas, United States
  • Johnson, Richard J., University of Colorado Denver, Greenwood Village, Colorado, United States
  • Leamon, Christopher P., Endocyte Inc, West Lafayette, Indiana, United States
Background

Macrophages are linked with the irreversible scarring that leads to end-stage renal disease. Since activated macrophages highly express a functional folate receptor β (FRβ), targeting this population of macrophages with folate-linked drugs could increase selectivity in the treatment of inflammatory diseases.

Methods

Accordingly, we synthesized and investigated the biologic activity of a novel folic acid-aminopterin conjugate (FA-AMT) designed to intracellularly deliver AMT specifically via the FR. The anti-inflammatory activity of FA-AMT was evaluated in a model of severe, macrophage-mediated anti-glomerular basement membrane glomerulonephritis in WKY rats.

Results

Toxicity assessment demonstrated that FA-AMT is not toxic (its maximum tolerated dose was 40-fold higher compared to unmodified AMT). We found that treatment with FA-AMT significantly attenuated kidney injury and preserved normal renal function. Glomerular proliferation, necrotizing lesion, crescent formation, tubulointersititial injury (TIN), and the number of tubular casts, a good indicator of chronic TIN injury, were markedly reduced in the FA-AMT-treatment group compared with the control group. FA-AMT reduced glomerular macrophage infiltration (52%) and decreased M1 macrophage phenotype without affecting M2 macrophages. Notably, interstitial macrophage accumulation that predicts progression of kidney injury was decreased in rats treated with FA-AMT. The expression of CCL2 and the pro-fibrotic cytokine TGF-β were reduced in nephritic glomeruli with FA-AMT treatment. Importantly, in rats treated with FA-AMT there was a significant reduction in the deposition of type I, III, and IV, collagens. Staining with specific anti-FRβ antibody showed no expression of this receptor in normal kidneys, however, in nephritic kidneys FRβ was mainly expressed on macrophages present in the crescents and also on macrophages within the glomerular capillaries. Notably, in rats treated with FA-AMT, the expression of FRβ was decreased and correlated with less macrophage infiltration and reduced crescent formation.

Conclusion

These findings suggest that targeting kidney activated macrophages attenuates inflammation and prevents progression of kidney injury and that because this is a FR-restricted specific treatment systemic immunosuppression can be prevented.

Funding

  • NIDDK Support