Estradiol suppresses type I collagen synthesis in mesangial cells via activation of activator protein-1

Background. Estradiol suppresses the synthesis of type I collagen by murine mesangial cells. However, neither the alpha(1)(I) nor the alpha(2)(I) coll agen gene contains an estrogen-response element. Because estradiol modulate s the transcription of several genes that lack an estrogen-response element but contain a regulatory activator protein-1 (AP-1) binding motif, we hypo thesized that AP-1 may mediate estradiol-induced suppression of type I coll agen synthesis. Methods. We measured type I collagen synthesis in murine me sangial cells exposed to estradiol, phorbol 12-myristate 13-acetate (an act ivator of AP-1), or curcumin (an inhibitor of AP-1). We also assessed the e ffects of estradiol on the steady-state level of c-fos and c-jun mRNA and o n the binding of mesangial cell nuclear extracts to an AP-1 consensus bindi ng site oligonucleotide. Results. Estradiol (10(-10) M to 10(-7) M) suppres sed type I collagen synthesis by murine mesangial cells in a dose-dependent manner (10(-7) M, 43.7 +/- 8.2% of control values, P < 0.001). Phorbol 12- myristate 13-acetate (10 mu M, four-hr exposure) also decreased type I coll agen in the media. In contrast, curcumin (1 mu M) increased type I collagen . Estradiol increased the steady-state level of c-fos mRNA twofold at 30 mi nutes, with a return to basal levels at one hour. This was associated with a greater than threefold increase in the binding of nuclear extracts from e stradiol-treated mesangial cells to an AP-1 consensus binding site oligonuc leotide. Estradiol-enhanced binding of nuclear extracts to the AP-1 oligonu cleotide was reversed by cycloheximide. Conclusions. These data suggest tha t estradiol suppresses collagen I synthesis by murine mesangial cells via e nhanced AP-1 activity.