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

Abstract

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.

Selective Stimulation of VEGFR2 Accelerates Progressive Renal Disease

“…39 Mesangial proliferation induced by Flk-sel therapy was associated with alterations in expression of PDGF/ PDGFR, which are potent mitotic factors for mesangial cells. 40 This finding is consistent with previous report. 41 Notably, VEGF-A is capable of signaling through PDGFRs, 42 and so our VEGF-A mutant might directly stimulate PDGF pathways in our animals, leading to alterations in mesangial cell biology.…”

A New Look at Platelet-Derived Growth Factor in Renal Disease

“…103 Mice with high circulating levels of PDGF-D after adenoviral transfection of the liver developed a severe mesangioproliferative glomerulopathy, characterized by enlarged glomeruli and a striking increase in glomerular cellularity. 104 Collectively, these data demonstrate potent roles of PDGF-B and -D in inducing mesangioproliferative changes as well as tubulointerstitial fibrosis in the case of PDGF-B.…”

“…107 The induction of mesangioproliferative changes was reproduced in healthy mice and rats by hepatic transfection with viral constructs encoding PDGF-B, resulting in elevated circulating levels of this isoform. 104 Finally, glomerular overexpression of PDGF-B also drove bone marrow-derived cells toward a mesangial-like phenotype in vivo. 108 At very high dosages (5 mg/kg), PDGF-BB infusion into rats induced dosage-dependent renal tubulointerstitial cell proliferation, myofibroblast formation, and fibrosis, which were reversible after PDGF-BB infusion was abrogated.…”

“…103 Similarly, adenoviral transfection of mouse liver with a construct encoding PDGF-C and causing elevated circulating levels of this isoform did not induce renal abnormalities. 104 A novel biologic role of PDGF-C, which has yet to be explored in the kidney, is a very potent induction of angiogenesis. 105 Infusion of recombinant PDGF-BB into healthy rats led to a selective increase of glomerular MC proliferation.…”

Imatinib Suppresses Cryoglobulinemia and Secondary Membranoproliferative Glomerulonephritis

“…[11][12][13][14][15][16] It is well established that the PDGF-B and -D isoforms induce glomerular mesangial cell proliferation through engagement of the PDGFR-␤. [17][18][19][20] Furthermore, it has been shown that glomerular cell proliferation and extracellular matrix expansion in TSLP-transgenic (TSLP-Tg) mice are closely associated with enhanced expression of PDGF-B and PDGFR-␤. 21 These data indicate that the PDGF ligand/receptor system is an attractive therapeutic target to ameliorate the glomerular injury in the TSLP-Tg MPGN model.…”