Transcriptional effects of Pentraxin-2 in fibrotic disease of the kidney

Pentraxin-2 (PTX-2) is a constitutive, anti-inflammatory, innate immune plasma protein whose circulating level is decreased in chronic human fibrotic diseases. Recent studies indicate that systemic delivery of recombinant PTX-2 inhibits inflammatory diseases associated with fibrosis by blocking pro-fibrotic macrophage activation and promoting anti-inflammatory and regulatory macrophages. Here we show that recombinant human PTX-2 (rhPTX-2) retards the progression of chronic kidney disease in Col4a3 mutant mice that develop Alport syndrome, reducing blood markers of kidney failure, enhancing lifespan by 20%, and improving histological signs of disease. Exogenously-delivered rhPTX-2 is detected in macrophages but is also found in tubular epithelial cells where it counteracts macrophage activation and is cytoprotective for the epithelium. We performed transcriptional profiling of whole kidney homogenates and human proximal tubule epithelial cells (PTECs) to identify pathways differentially activated or suppressed in response to treatment with PTX-2. Computational analysis of genes regulated by rhPTX-2 identified the transcriptional regulator c-Jun and its binding partners, which form AP-1 complexes, as a central target for the function of rhPTX-2. Accordingly, PTX-2 attenuates c-Jun activation 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.

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Nakagawa N, Barron L, Gomez IG, Johnson BG, Roach AM, Kameoka S, Jack RM, Lupher ML Jr, Gharib SA, Duffield JS