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Exogenous PDGF-D Is a Potent Mesangial Cell Mitogen and Causes a Severe Mesangial Proliferative Glomerulopathy

Kelly L. Hudkins^*, Debra G. Gilbertson, Matthew Carling^*, Sekiko Taneda^*, Steven D. Hughes, Matthew S. Holdren, Thomas E. Palmer, Stavros Topouzis, Aaron C. Haran, Andrew L. Feldhaus and Charles E. Alpers^*

*University of Washington, Seattle, Washington; and Zymogenetics, Inc., Seattle, Washington

Correspondence to Dr. Charles E. Alpers, University of Washington, Department of Pathology, Box 357470, Seattle, WA 98195. Phone: 206-598-6409; Fax: 206-543-3644; E-mail: calp{at}u.washington.edu

ABSTRACT. The PDGF family consists of at least four members, PDGF-A, -B, -C, and -D. All of the PDGF isoforms bind and signal through two known receptors, PDGF receptor- and PDGF receptor-, which are constitutively expressed in the kidney and are upregulated in specific diseases. It is well established that PDGF-B plays a pivotal role in the mediation of glomerular mesangial cell proliferation. However, little is known of the roles of the recently discovered PDGF-C and -D in mediating renal injury. In this study, adenovirus constructs encoding PDGF-B, -C, and -D were injected into mice. Mice with high circulating levels of PDGF-D developed a severe mesangial proliferative glomerulopathy, characterized by enlarged glomeruli and a striking increase in glomerular cellularity. The PDGF-B–overexpressing mice had a milder proliferative glomerulopathy, whereas the mice overexpressing PDGF-C and those that received adenovirus alone showed no measurable response. Mitogenicity of PDGF-D and -B for mesangial cells was confirmed in vitro. These findings emphasize the importance of engagement of PDGF receptor- in transducing mesangial cell proliferation and demonstrate that PDGF-D is a major mediator of mesangial cell proliferation. Finally, this approach has resulted in a unique and potentially valuable model of mesangial proliferative glomerulopathy and its resolution.

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