Pentraxin-2 suppresses c-Jun/AP-1 signaling to inhibit progressive fibrotic disease
Naoki Nakagawa, Luke Barron, Ivan G. Gomez, Bryce G. Johnson, Allie M. Roach, Sei Kameoka, Richard M. Jack, Mark L. Lupher Jr., Sina A. Gharib, Jeremy S. Duffield
Naoki Nakagawa, Luke Barron, Ivan G. Gomez, Bryce G. Johnson, Allie M. Roach, Sei Kameoka, Richard M. Jack, Mark L. Lupher Jr., Sina A. Gharib, Jeremy S. Duffield
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Research Article Immunology Inflammation

Pentraxin-2 suppresses c-Jun/AP-1 signaling to inhibit progressive fibrotic disease

Abstract

Pentraxin-2 (PTX-2), also known as serum amyloid P component (SAP/APCS), is a constitutive, antiinflammatory, innate immune plasma protein whose circulating level is decreased in chronic human fibrotic diseases. Here we show that recombinant human PTX-2 (rhPTX-2) retards progression of chronic kidney disease in Col4a3 mutant mice with Alport syndrome, reducing blood markers of kidney failure, enhancing lifespan by 20%, and improving histological signs of disease. Exogenously delivered rhPTX-2 was detected in macrophages but also in tubular epithelial cells, where it counteracted macrophage activation and was cytoprotective for the epithelium. Computational analysis of genes regulated by rhPTX-2 identified the transcriptional regulator c-Jun along with its activator protein–1 (AP-1) binding partners as a central target for the function of rhPTX-2. Accordingly, PTX-2 attenuates c-Jun and AP-1 activity, and reduces expression of AP-1–dependent inflammatory genes in both monocytes and epithelium. Our studies therefore identify rhPTX-2 as a potential therapy for chronic fibrotic disease of the kidney and an important inhibitor of pathological c-Jun signaling in this setting.

Authors

Naoki Nakagawa, Luke Barron, Ivan G. Gomez, Bryce G. Johnson, Allie M. Roach, Sei Kameoka, Richard M. Jack, Mark L. Lupher Jr., Sina A. Gharib, Jeremy S. Duffield

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Figure 2

rhPTX-2 prevents glomerulosclerosis, glomerular basement membrane accumulation, and podocyte loss.

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rhPTX-2 prevents glomerulosclerosis, glomerular basement membrane accumu...
(A) Representative images of kidney cortex at 9 weeks of age showing periodic acid–Schiff– stained (PAS-stained) images of glomeruli with glomerulosclerosis (white arrows); WT-1 immunofluorescence for podocytes within glomeruli (dotted lines); electron microscopy (EM) images of glomerular capillary loops showing severe glomerular basement membrane (GBM) thickening with humps, and podocyte effacement (loss of processes) in vehicle-treated Col4a3–/– mice. rhPTX-2–treated Col4a3–/– mice show areas of preserved basement membrane and partial foot process effacement, but small classical basement membrane humps persist. U, urinary space; P, podocyte; Pp, podocyte processes; L, capillary lumen; EC, endothelial cell. (B) Glomerulosclerosis score ranged from none (0) to >75% of glomeruli affected (4). (C) WT-1+ podocytes per glomerular cross-section. (D) GBM thickness. Scale bars: 50 μm (light) or 500 nm (EM). n = 6–12/group. *P < 0.05, **P < 0.01 (ANOVA with post hoc testing for multiple comparisons). VEH, vehicle.