IDENTIFICATION OF PLATELET-DERIVED-GROWTH-FACTOR-A AND PLATELET-DERIVED-GROWTH-FACTOR-B CHAINS IN HUMAN RENAL VASCULAR REJECTION

Platelet-derived growth factor (PDGF) exists as a dimer composed of tw o homologous but distinct peptides termed PDGF-A and -B chains, and ma y exist as AA, AB, and BB isoforms. The PDGF-B chain has been implicat ed as a mediator of renal vascular rejection by virtue of up-regulated expression of its receptor, PDGF beta-receptor, in affected arteries. A role for PDGF-A chain in mediating intimal proliferation has been s uggested in human atherosclerosis (Rekhter MD, Gordon D: Does platelet -derived growth factor-A chain stimulate proliferation of arterial mes enchymal cells in human atherosclerotic plaques? Circ Res 1994, 75:410 ), but no studies of this molecule in human renal allograft injury hav e been reported to date. We used two polyclonal antisera to detect exp ression of PDGF-A chain and one monoclonal antibody to detect PDGF-B c hain by immunohistochemistry in fixed, paraffin-embedded tissue from 1 ) normal adult kidneys, 2) a series of renal transplant biopsies chose n to emphasize features of vascular rejection, and 3) allograft nephre ctomies. Immuno-histochemistry was correlated with in situ hybridizati on on adjacent, formalin fixed tissue sections from nephrectomies util izing ribo-probes made from PDGF-A and -B chain cDNA. PDGF-A chain is widely expressed by medical smooth muscle cells of normal and rejectin g renal arterial vessels of al sizes by immunohisto-chemistry and in s itu hybridization. PDGF-A chain is also expressed by a population of s mooth muscle cells (shown by double immuno-labeling with an antibody t o alpha-smooth muscle actin) comprising the intima in chronic vascular rejection. In arteries demonstrating acute rejection, up-regulated ex pression of PDGF-A chain by endothelial cells was detected by both imm unohistochemistry an din situ hybridization. In contrast, PDGF-B chain was identified principally in filtrating monocytes within the rejecti ng arteries, similar to its localization in infiltrating monocytes in human atherosclerosis. Although less prominent than the case for PDGF- A chain, PDGF-B chain also was present in medical and intimal smooth m uscle cells in both rejecting and nonrejecting renal arteries. PDGF-A and -B chains have now been localized at both the mRNA and protein lev els to the intimal proliferative lesions of vascular rejection. These peptides, which are known stimuli for smooth muscle cell migration and proliferation in experimental vascular injury, may have similar stimu latory effects on smooth muscle cells in an autocrine and/or paracrine manner to promote further intimal expansion and lesion progression in this form of human vasculopathy.