The synthesis of renin and other biologically active polypeptides in the granular convoluted tubule cells of the mouse submandibular gland (SMG) is regulated by androgen and thyroid hormones. In this study genetically hypothyroid (hyt/hyt) mice carrying a single renin structural gene (Ren-1) were used to investigate the mechanism of hormonal action in mouse SMG. Treatment of female mice with 5α-dihydrotestosterone (DHT) and/or thyroxine (T4) enhanced renin-1 activity and increased renin-1 mRNA, determined by Northern analysis. Compared to euthyroid (hyt/ +) littermates, hyt/hyt mice had lower basal levels of renin-1 mRNA and a blunted response to either hormone alone. DHT and T4 acted synergistically to increase renin-1 activity and renin-1 mRNA in the SMG of hyt/hyt females. Furthermore, levels of renin-1 activity and renin-1 mRNA varied concordantly in the SMG of these animals. These data indicate that androgen and thyroid hormones influence levels of renin-1 in mouse SMG primarily by regulating the amount of renin-1 mRNA available for translation.