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Neutralization of Macrophage-Stimulating Protein Ameliorates Renal Injury in Anti–Thy 1 Glomerulonephritis

Teresa Rampino^*, Grazia Soccio^*, Marilena Gregorini^*, Cristina Guidetti^*, Maddalena Marasà^*, Milena Maggio^*, Vincenzo Panichi, Massimiliano Migliori, Carmelo Libetta^* and Antonio Dal Canton^*

^* Unit of Nephrology, Dialysis and Transplantation, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo and University of Pavia, Pavia, and Department of Internal Medicine and Neuroscience (Pharmacology Section), University of Pisa, Pisa, Italy

Address correspondence to: Dr. Teresa Rampino, Unit of Nephrology, Dialysis, Transplantation, IRCCS Policlinico San Matteo, Pavia, Italy. Phone: +39-0382-422037; Fax: +39-0382-526341; t.rampino{at}smatteo.pv.it

Received for publication June 30, 2006. Accepted for publication February 13, 2007.

Macrophage-stimulating protein (MSP) is a scatter factor that causes cell proliferation and migration, and receptor origin nantaise (RON) is its receptor. RON is expressed in macrophages and mesangial cells, and MSP is produced by renal tubular cells. This study investigated whether MSP/RON participate in the pathogenesis of anti–Thy 1 nephritis, a glomerular disease that is characterized by invasion of circulating monocytes into glomeruli and migration and proliferation of mesangial cells. In vivo, renal function and histopathology were studied in rats that had anti–Thy 1 disease and were untreated and treated with a neutralizing anti-MSP antibody. In vitro, whether monocytes express RON and whether MSP has a chemotactic effect on monocytes were studied. In vivo, in anti–Thy 1 disease, MSP was expressed de novo in glomeruli, and neutralization of MSP attenuated the rise in serum creatinine and proteinuria, stopped glomerular neutrophil and monocyte influx, protected from glomerular injury, and lessened mesangial cell overgrowth. In vitro, unstimulated monocytes did not express RON, but the stimulation with LPS induced de novo RON expression. LPS-stimulated monocytes were attracted by MSP. These results demonstrate a pathogenic role of the MSP/RON system in anti–Thy 1 nephritis.

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673