Exogenous PDGF-D is a potent mesangial cell mitogen and causes a severe mesangial proliferative glomerulopathy.
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.
Hudkins
Kelly L
KL
University of Washington, Seattle, Washington 98195, USA.
Gilbertson
Debra G
DG
Carling
Matthew
M
Taneda
Sekiko
S
Hughes
Steven D
SD
Holdren
Matthew S
MS
Palmer
Thomas E
TE
Topouzis
Stavros
S
Haran
Aaron C
AC
Feldhaus
Andrew L
AL
Alpers
Charles E
CE
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
D008222:Lymphokines; D008934:Mitogens; C498951:Pdgfd protein, mouse; D010982:Platelet-Derived Growth Factor