TARGETING FROUNT INHIBITS MACROPHAGE MIGRATION AND ACTIVATION SIGNAL, ATTENUATING GLOMERULAR INFLAMMATION AND TUBULOINTERSTITIAL FIBROSIS.

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Abstract Title *

TARGETING FROUNT INHIBITS MACROPHAGE MIGRATION AND ACTIVATION SIGNAL, ATTENUATING GLOMERULAR INFLAMMATION AND TUBULOINTERSTITIAL FIBROSIS.

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Co-author 1

Etsuko Toda t-etsuko@nms.ac.jp Nippon Medical School Laboratory for Morphological and Biomolecular Imaging Tokyo Japan *

Co-author 2

Yoko Endo y-endo2@nms.ac.jp Nippon Medical School Department of Analytic Human Pathology Tokyo Japan -

Co-author 3

Kazuhiro Takeuchi k-takeuchi@nms.ac.jp Nippon Medical School Department of Analytic Human Pathology Tokyo Japan -

Co-author 4

Hideaki Kuno h-kuno@nms.ac.jp Nippon Medical School Department of Analytic Human Pathology Tokyo Japan -

Co-author 5

Yuya Terashima tera@rs.tus.ac.jp Tokyo University of Science Division of Molecular Regulation of InﬂResearch Institute for Biomedical Sciences Chiba Japan -

Co-author 6

Akira Shimizu ashimizu@nms.ac.jp Nippon Medical School Department of Analytic Human Pathology Tokyo Japan -

Co-author 7

Co-author 8

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Co-author 10

Co-author 11

Co-author 12

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Introduction

Monocyte/macrophage (Mo/Mφ) accumulation exacerbates inflammation and fibrosis, contributing to renal injury in both glomerular and tubulointerstitial compartments. However, safe methods to control their deleterious actions without compromising host defense mechanisms remain to be established. FROUNT, an intracellular molecule highly expressed in Mo/Mφ, binds to the chemokine receptors CCR2 and CCR5 to amplify cell migration signaling. In this study, we investigated the therapeutic potential of targeting FROUNT in rodent models representing both glomerular and tubulointerstitial disease.

Methods

We tested disulfiram, an existing anti-alcoholism drug, which we identified to possess FROUNT inhibitory activity. We employed two rodent models of kidney disease: a glomerulonephritis model (for glomerular injury assessment) and a diabetic nephropathy (DN) model (for tubulointerstitial injury assessment). In the glomerulonephritis model, the effects of disulfiram on crescent formation, albuminuria, and glomerular Mo/Mφ accumulation were assessed. Peripheral blood monocyte counts were also assessed. In the DN model, tubulointerstitial Mo/Mφ infiltration and collagen deposition were evaluated. Furthermore, macrophage-specific FROUNT-deficient mice (LysM-Cre;FROUNT-flox) were also utilized in the DN model.

Results

In the glomerulonephritis model, disulfiram administration markedly suppressed crescent formation and albuminuria. Inflammation-driven Mo/Mφ accumulation in the glomeruli was significantly reduced. In contrast, peripheral blood monocyte counts remained unchanged. In the DN model, which is characterized by tubulointerstitial damage, disulfiram administration reduced Mo/Mφ infiltration and attenuated tubulointerstitial fibrosis (collagen deposition). Macrophage-specific FROUNT-deficient mice also exhibited a similar attenuation of fibrosis, thus providing genetic evidence for the contribution of FROUNT to macrophage-dependent pathogenesis.

Conclusion

FROUNT represents a promising novel therapeutic target. Targeting FROUNT suppresses inflammation-driven macrophage accumulation in diseased kidneys, thereby inhibiting inflammation and fibrosis in both the glomerular and tubulointerstitial compartments, crucially without affecting peripheral blood monocyte counts.

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