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Y-Box Protein 1 Mediates PDGF-B Effects in Mesangioproliferative Glomerular Disease

Claudia R.C. van Roeyen^*,, Frank Eitner^*,, Sandra Martinkus^*, Sabrina R. Thieltges^*, Tammo Ostendorf^*, Dirk Bokemeyer, Bernhard Lüscher, Juliane M. Lüscher-Firzlaff, Juergen Floege^* and Peter R. Mertens^*

^* Department of Nephrology and Immunology, RWTH Aachen University, Aachen, Germany; Augusta Krankenhaus Bochum, Bochum, Germany; and Division of Biochemistry and Molecular Biology, Institute of Biochemistry, RWTH Aachen University, Aachen, Germany

Address correspondence to: Dr. Peter R. Mertens, Medical Clinic II, University Hospital Aachen, Pauwelsstrasse 30, 52057 Aachen, Germany. Phone: +49-241-8089532; Fax: +49-241-8082446; E-mail: pmertens{at}ukaachen.de

Received for publication November 27, 2004. Accepted for publication July 5, 2005.

The pivotal role of PDGF-B for mesangioproliferative glomerular disease is well established. Here, Y-box protein-1 (YB-1) was identified as a downstream signaling target of PDGF-B. In healthy kidney cells, YB-1 was located predominantly within the nuclear compartment. Subsequent to PDGF-B infusion and in the course of anti–Thy1.1-induced mesangioproliferative glomerulonephritis, relocalization of YB-1 into the cytoplasm was observed. In experimental models that lack profound mesangial cell proliferation (e.g., Puromycin-nephrosis, passive Heyman nephritis, spontaneous normotensive nephrosclerosis, hyperlipidemic diabetic nephropathy), YB-1 remained nuclear. This translocation coincided with upregulation of YB-1 protein levels within the mesangial compartment. Increased YB-1 expression and subcellular shuttling was dependent on PDGF-B signaling via the mitogen-activated protein kinase pathway because these alterations were prevented by specific PDGF aptamers and the mitogen-activated protein kinase pathway inhibitor U0126. Furthermore, PDGF-B strongly induced YB-1 expression in vitro. This induction was important because RNAi-dependent knockdown of YB-1 abolished the mitogenic PDGF-B effect. Taken together, YB-1 seems to represent a specific and necessary PDGF-B target in mesangioproliferative glomerular disease.

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