Abstract
Since activated macrophages express a functional folate receptor β (FRβ), targeting this macrophage population with folate-linked drugs could increase selectivity to treat inflammatory diseases. Using a macrophage-mediated anti-glomerular basement membrane (anti-GBM) glomerulonephritis (GN) in WKY rats, we investigated the effect of a novel folic acid-aminopterin (AMT) conjugate (EC2319) designed to intracellularly deliver AMT via the FR. We found that treatment with EC2319 significantly attenuated kidney injury and preserved renal function. Kidney protection with EC2319 was blocked by a folate competitor, indicating that its mechanism of action was specifically FRβ-mediated. Notably, treatment with methotrexate (MTX), another folic acid antagonist related to AMT, did not protect from kidney damage. EC2319 reduced glomerular and interstitial macrophage infiltration and decreased M1 macrophage recruitment but not M2 macrophages. The expression of CCL2 and the pro-fibrotic cytokine TGF-β were also reduced in nephritic glomeruli with EC2319 treatment. In EC2319-treated rats, there was a significant decrease in the deposition of collagens. In nephritic kidneys, FRβ was expressed on periglomerular macrophages and macrophages present in the crescents, but its expression was not observed in normal kidneys. These data indicate that selectively targeting the activated macrophage population could represent a novel means for treating anti-GBM GN and other acute crescentic glomerulonephritis.
Highlights
Inflammation is a key factor in the induction and progression of glomerulonephritis (GN) and other kidney diseases [1,2]
EC2319 reduced proteinuria compared to the control group (Ctrl 109.25 ± 11.8 vs. 49.17 ± 2.6 mg/24 h, p < 0.001) (Figure 3B). These results indicate that treatment with EC2319 at the acute phase of anti-glomerular basement membrane (GBM) GN confers kidney protection from damage
EC2319 treatment attenuated the infiltration of these macrophages by 52% in the glomeruli (74 ± 3.1 vs. 35.5 ± 3.75, p < 0.01) and 48.1% in the interstitium (147.03 ± 4.19 vs. 76.3 ± 3.36, p < 0.01) compared with the untreated group (Figure 4A,B)
Summary
Roncal-Jiménez 1 , Makoto Miyazaki 1 , Shinobu Miyazaki-Anzai 1 , Gabriel Cara-Fuentes 1 , Ana Andres-Hernando 1 , Miguel Lanaspa 1 , Richard J.
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