title: Exogenous PDGF-D is a potent mesangial cell mitogen and causes a severe mesangial proliferative glomerulopathy.
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-alpha and PDGF receptor-beta, 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-beta 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.
authors.affiliation: University of Washington, Seattle, Washington 98195, USA.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Hudkins
authors.forename: Debra G
authors.initials: DG
authors.lastname: Gilbertson
authors.forename: Matthew
authors.initials: M
authors.lastname: Carling
authors.forename: Sekiko
authors.initials: S
authors.lastname: Taneda
authors.forename: Steven D
authors.initials: SD
authors.lastname: Hughes
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Holdren
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Palmer
authors.forename: Stavros
authors.initials: S
authors.lastname: Topouzis
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Haran
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Feldhaus
authors.forename: Charles E
authors.initials: CE
authors.lastname: Alpers
mesh_terms: D000818:Animals; D005260:Female; D005920:Glomerular Mesangium / Q000166:cytology* / Q000187:drug effects*; D015433:Glomerulonephritis, Membranous / Q000139:chemically induced*; D008222:Lymphokines / Q000096:biosynthesis / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008934:Mitogens / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis / Q000494:pharmacology*; D012720:Severity of Illness Index; D013997:Time Factors
chemical_list: D008222:Lymphokines; D008934:Mitogens; C498951:Pdgfd protein, mouse; D010982:Platelet-Derived Growth Factor