Thyroid Hormone (3,5,3′-Triido-l-Thyronine) Masking/Inversion of Stimulatory Effect of Androgen on Expression of mk1, a True Tissue Kallikrein, in the Mouse Submandibular Gland*

Abstract

We studied hormonal regulation of the expression of mkl, a true tissue kallikrein, in the submandibular gland (SMG) of ICR, C3H/ HeN, and F1 (mice from male C3H/HeN x female ICR and in the ones from male ICR x female C3H/HeN). In these mouse strains, mk1 was low in content in males, abundant in females, and increased remarkably by castration of males. In the case of ICR and both F1 mice, injection of 5alpha-dihydrotestosterone (DHT) reduced the mkl level of castrated and female mice. However, the mkl content in female C3H/ HeN mice (or castrated C3H/HeN) was further increased by DHT. To investigate the real action of DHT on mk1 expression, we examined the effects of adrenoectomy/glucocorticoid (dexamethasone, Dex) administration; DHT administration into castrated and adrenoectomized mice; ovariectomy/female hormone (17beta-estradiol, progesterone) administration; and hypophysectomy/combinatory administration of DHT, Dex, and thyroid hormone (3,5,3'-triiodo-L-thyronine, T3) on the mk1 expression in the SMG of ICR mice. Adrenoectomy or ovariectomy did not change the characteristic pattern of mk1 expression in male and female ICR mice. In hypophysectomized (Hypox) ICR male mice, the mk1 content was increased to the same level as in normal ICR females, and DHT administration into the Hypox mice further increased the mk1 level. However, combinatory administration of DHT + T3 or of DHT + T3 + Dex into the Hypox mice lowered the mkl content to the level of normal ICR males, whereas T3 single administration had no effect. Dex single administration into the Hypox mice increased the mkl level to an even higher than that observed with DHT administration. The mk1 level in Hypox mice was not significantly changed by coadministration of Dex with T3. From these results, we conclude that 1) mk1 expression is fundamentally stimulated by androgen (DHT) as are other mk isozymes, such as mk9, mk13, mk22, and mk26 in the mouse SMG, 2) the effect (stimulatory) of DHT on mk1 expression becomes, however, inverted (inhibitory) in the presence of T3. Although the serum T3 level of C3H/HeN female (0.52 ng/ml) was not significantly different from that of C3H/HeN males or ICR mice, coadministration of T3 into C3H/HeN females with a fixed amount of DHT (20 mg/kg body weight) dose dependently repressed the DHT-induced increase in mkl expression, suggesting the lower sensitivity of C3H/HeN females to T3.

Strain‐Specific and Endocrine Control of Granular Convoluted Tubule Cells and Epidermal Growth Factor Expression in the Mouse Submandibular Gland

“…It is suspected that a low EGF concentration in SMGs may be caused by a lower level of hormones in blood. However, according to previous studies, serum T 3 levels do not vary significantly between low and high EGF strains in mature adults: approximately 0.45 ng/ml and 0.52 ng/ml in C3H/HeN males and females, respectively, and 0.53 ng/ml and 0.45 ng/ml in ICR males and female, respectively (Kurihara et al,1999), 0.66 ng/ml in C57BL/6J males and 0.61 ng/ml in C3H/HeN males (Maia et al,1995), and 0.72 ng/ml in ICR males (Burgi et al,1986). These facts suggest that serum T 3 levels are not responsible for the strain‐specific low or high concentration of EGF in SMG.…”

“…Concretely, when the allele Rnr s from a donor AKR/J, a high SMG renin strain, was included on the genetic background of C57L/J, a low SMG renin strain, SMG renin activity in the F1 progeny was intermediate between that of the parent strains, suggesting that SMG renin is controlled by genes located in the same region of chromosome 1 (Wilson et al,1981). Furthermore, using the same mating pairs as those used in the present study, either type of F1 progeny inherited all of the kallikrein isozymes from either of the parent strains (Kurihara et al,1999). These two previous mating experiments suggest that EGF is directly/indirectly under genetic regulation similar to that seen for SMG renin and that the F1 progeny seem to inherit genetic characteristics from both parent strains.…”

“…In contrast, the mK1 concentration in an outbred ICR strain, which was classified into the high renin group, was higher in the SMGs of females than in males (Hosoi et al,1983). Furthermore, the response of mK1 expression to androgen was suggested to be opposite between ICR and C3H/HeN females, and such a difference may be caused by the lesser sensitivity of C3H/HeN females to thyroid hormone (Kurihara et al,1999). To our knowledge, the renin regulator ( Rnr ) gene and the synthesis of GCT‐specific secretory products are unrelated, other than the involvement of renin.…”

Interference of kallikrein 1b26 (klk1b26) translation by microRNA specifically expressed in female mouse submandibular glands: an additional mechanism for sexual dimorphism of klk1b26 protein in the glands

“…All hormone injections were made subcutaneously six times with a 1-day interval at a dose of 20 mg/kg DHT. At 1 day after the last hormone injection, the animals were killed by cervical dislocation and their SMGs were removed [ 6 ].…”

“…One of the most prominent characteristics of these bioactive substances in mouse SMGs is the sex difference in their content [ 4 - 8 ]. The expression of klk9, klk22, and klk1b26 proteins in the ICR mouse is androgen responsive: the contents of these kallikreins are much higher in the male SMG than in the female one, castration decreases their contents to levels similar to the female ones, and 5α-dihydrotestosterone administration to females or castrated animals increases the content of these proteins [ 4 - 6 ]. This sex difference is thought to be due to increased mRNA synthesis stimulated by androgen [ 9 , 10 ].…”