Dual roles of CCL5 on podocytes and macrophages in glomerular injury

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Dual roles of CCL5 on podocytes and macrophages in glomerular injury

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Co-author 1

Issei Okunaga i_okunaga@chiba-u.jp Graduate School of Medicine, Chiba University Nephrology Chiba Japan *

Co-author 2

Ika N Kadariswantiningsih ikanindya@gmail.com Graduate School of Medicine, Chiba University Nephrology Chiba Japan -

Co-author 3

Maulana A Empitu m.a.empitu@gmail.com Graduate School of Medicine, Chiba University Nephrology Chiba Japan -

Co-author 4

Kaho Yamasaki kahoyamasaki@chiba-u.jp Graduate School of Medicine, Chiba University Nephrology Chiba Japan -

Co-author 5

Masashi Aizawa m_aizw@chiba-u.jp Graduate School of Medicine, Chiba University Nephrology Chiba Japan -

Co-author 6

Hanae Wakabayashi hawakaba@chiba-u.jp Graduate School of Medicine, Chiba University Nephrology Chiba Japan -

Co-author 7

Atsuhiro Taguchi ataguchi@chiba-u.jp Graduate School of Medicine, Chiba University Nephrology Chiba Japan -

Co-author 8

Katsuhiko Asanuma kasanuma@chiba-u.jp Graduate School of Medicine, Chiba University Nephrology Chiba Japan -

Co-author 9

Co-author 10

Co-author 11

Co-author 12

Co-author 13

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Introduction

We previously reported that Notch2 activation in mouse reduces podocyte damage in vivo (Nature Commun. 2014; 5: 3296). Here, we identified C-C motif chemokine ligand 5 (CCL5) as a downstream effector of Notch2 activation. CCL5 is a secreted protein that acts on macrophages (Mφ), T cells, and epithelial cells, but its role in glomerular injury remains controversial. While one study showed that a functional CCL5 antagonist attenuates glomerulonephritis, another reported that it exacerbates glomerular damage in disease models. To clarify these conflicting observations, we investigated the cell type–specific functions of CCL5 in podocytes and bone marrow-derived cells using in vitro and in vivo approaches.

Methods

We performed immunostaining of human kidney samples to examine CCL5 expression in glomerular disease. CCL5 knockout (KO) podocytes and mice were generated. Cultured wild-type (WT) podocytes and CCL5 KO podocytes were treated with adriamycin (ADR), and apoptosis rates were evaluated. WT and CCL5 KO mice were injected with ADR to induce nephropathy, followed by assessment of kidney pathology. To distinguish the contribution of CCL5 in intrinsic renal cells versus bone marrow-derived macrophages, bone marrow transplantation between WT and CCL5 KO mice was performed.

Results

ADR-induced injury in cultured WT podocytes was ameliorated by exogenous CCL5 administration and exacerbated by CCL5 depletion, suggesting a cell-autonomous protective role of CCL5 in ADR-injured podocytes in vitro. We further found that CCL5 expression in glomeruli was upregulated in patients with glomerular disease and in ADR-induced nephropathy mice. In contrast to the in vitro results, ADR-induced nephropathy was ameliorated in CCL5 KO mice in vivo. Bone marrow chimera experiments revealed that podocyte-derived CCL5 confers protection, whereas CCL5 from bone marrow-derived macrophages aggravates glomerular inflammation.

Conclusion

CCL5 plays dual roles in experimental nephropathy—protective in podocytes but pathogenic through macrophage activation. These results suggest that CCL5 has ambivalent roles in glomerular diseases, acting in a cell type-dependent manner and offering insight into cell-specific chemokine targeting as a potential therapeutic approach.

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