The kallikrein-Kinin System in the pituitary gland is involved in lactotroph function and controlled by dopamine and estradiol

Abstract

TGFβ1 is a potent inhibitor of lactotroph cell proliferation and prolactin (PRL) secretion and Tissue Kallikrein (KLK1) was described as an important activator of latent TGFβ1 in vivo. The Kallikrein-Kinin System (KKS) is complex; kininogens are cleaved by KLK1, releasing kinins, which exert their effect throw its receptors B1R and B2R. Whereas B2R is constitutively expressed, B1R is inducible in pathological conditions. We have previously found that the pituitary expression of most components of the KKS, as well as local TGFβ1 activity, is reduced in prolactinomas. Then we postulate that the recovery of pituitary KKS, could improve local TGFβ1 activity counteracting prolactinoma development. To this end, we first deepen the study of the pituitary KKS regulation by dopamine and estradiol and the pituitary cell types expressing kinins receptors. Female mice lacking the dopamine receptor type 2 (Drd2KO, prolactinoma) vs WT counterpart were used. 1- Double immunofluorescences were performed to assay B2R expression in different pituitary cell-types in WT females. We found that lactotrophs, somatotrophs and gonadotrophs express B2R. 2- Adult females were injected with E2 valerate (0.2mg/kg, sc), cabergoline (DA agonist, 2mg/Kg, ip), sulpiride (DA antagonist, 5mg/kg, ip) or vehicle (castor oil or saline) and were sacrificed after 3 hours. Pituitary expression of KKS components was evaluated by RTqPCR. We found that E2 exerts a negative regulation of Klk1, b2r and b1r expression in WT females, but this control is lost in Drd2KO. On the contrary, DA exerts a positive regulation of Klk1 expression but negatively regulates b2r expression in WT females. We conclude that the positive DA-regulation exercised on the pituitary KLK1 expression is lost in the Drd2KO pituitary, reducing KLK1 local activity, reducing TGFβ1 activation, and contributing to prolactinoma development. The improvement of pituitary KKS activity could represent a novel treatment for resistant prolactinomas.