Alport Syndrome Improved by Pentraxin-2 in Animal Model Study

Shelly Rae Rich, PhD avatar

by Shelly Rae Rich, PhD |

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Alport kidney damage study

Scientists have found that a recombinant human protein, pentraxin-2 (rhPTX-2), slows progression of kidney disease in mice with Alport syndrome, extends lifespan by 20% and reduces blood markers indicating kidney failure. These findings suggest a potential alternative therapy for chronic fibrotic kidney disease.

Prior research has suggested that PTX-2 protects against inflammation and autoimmunity, and that circulating levels of PTX-2 in patients with chronic fibrotic disease are lower than normal, further implicating the deficiency may be contributing to the disease. Also, recent clinical trials using rhPTX-2 have demonstrated improvements in patients of lung and bone marrow fibrotic diseases.

Published in JCI Insight, the study, “Pentraxin-2 suppresses c-Jun/AP-1 signaling to inhibit progressive fibrotic disease,” used an animal model to examine efficacy and mechanisms of rhPTX-2.

The researchers used a mutated strain of mice (Col4a3 gene mutant) that exhibit pathological features of human Alport syndrome including glomerulosclerosis (scarring of kidney cells), tubulointerstitial fibrosis and intense promotion of inflammatory macrophages (immune cells). The researchers administered the mice with intraperitoneal injections of rhPTX-2 (daily for first three days, then twice per week), beginning 24 days after birth and ending at six or nine weeks.

They found progression of Alport syndrome was slowed, lifespan increased, histological signs improved and key blood markers of kidney disease were reduced. Additionally, rhPTX-2 was found in macrophages and tubular epithelial cells, counteracting macrophage activation and protecting the epithelial cells.

Genetic analysis of signaling and regulatory genes determined that c-Jun, a gene implicated in many diseases, and its activator protein-1 (AP-1) were targeted by rhPTX-2, therefore attenuating c-Jun and AP-1 activity. There was decreased expression of AP-1-dependent inflammatory genes in both monocytes and epithelial cells.

Although the c-Jun/AP-1 signaling is clearly identified in the study as the direct target of rhPTX-2, further studies will need to be done to elucidate the intermediaries (enzymes) in the mechanism.

This study, along with prior research, reemphasizes “the potent effect of PTX-2 on inhibiting M1 activation of macrophages while promoting their beneficial reparative functions.”

The researchers conclude that “rhPTX-2 administration is an effective therapy to counteract the progression of Alport nephropathy and enhance survival in mice.” While PTX-2 inhibits macrophage activation in the kidney, it also has anti-inflammatory properties and directly protects tubular epithelial cells that restore tubular kidney cell functions.


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