A novel treatment for glomerular disease: Targeting the activated macrophage folate receptor with a trojan horse therapy in rats

Gabriela E. Garcia, Yingjuan J. Lu, Luan D. Truong, Carlos A. Roncal-Jiménez, Makoto Miyazaki, Shinobu Miyazaki-Anzai, Gabriel Cara-Fuentes, Ana Andres-Hernando, Miguel Lanaspa, Richard J. Johnson, Christopher P. Leamon

Research output: Contribution to journalArticlepeer-review

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) glomeru-lonephritis (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.

Original languageEnglish (US)
Article number2113
JournalCells
Volume10
Issue number8
DOIs
StatePublished - Aug 2021

Keywords

  • Aminopterin
  • Fibrosis
  • Folate receptor
  • Glomerulonephritis
  • Inflammation
  • Macrophages

ASJC Scopus subject areas

  • Medicine(all)

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