EGF AND TGF-BETA REGULATE NEUTRAL ENDOPEPTIDASE EXPRESSION IN RENAL VASCULAR SMOOTH-MUSCLE CELLS

We recently reported that neutral endopeptidase (NEP) expression on re nal vascular smooth muscle cells (VSMC) was downregulated in the prese nce of serum. Here we examine the role of epidermal growth factor (EGF ) and transforming growth factor-beta(1) (TGF-beta) in this downregula tion and the consequences of the changes in NEP activity on their mito genic effects. EGF inhibited NEP activity, whereas TGF-beta was stimul atory. Expression of the enzyme was studied by measuring the binding o f [I-125]RB-104, a specific NEP inhibitor, and the fluorescence intens ity of NEP-labeled cells. Both parameters were decreased by EGF and we re increased by TGF-beta. NEP mRNA expression in EGF-treated cells was reduced after 48 h. In contrast, it was increased in TGF-beta-treated cells. Interestingly, NEP inhibition influenced the mitogenic effect of EGF. Indeed, thiorphan, an NEP inhibitor, and an anti-NEP antibody decreased EGF-dependent [H-3]thymidine incorporation and cell prolifer ation by similar to 50%. TGF-beta had no effect on VSMC growth. These results indicate that EGF but not TGF-beta participates in the downreg ulatory potency of serum on NEP expression in VSMC. They also demonstr ate that the full effect of EGF on VSMC proliferation depends on intac t NEP activity.