Aldo Keto Reductase 1B7 and Prostaglandin F-2 alpha Are Regulators of Adrenal Endocrine Functions

作者：Lambert Langlais Sarah^*; Pointud Jean Christophe; Lefrancois Martinez Anne Marie; Volat Fanny; Manin Michele; Coudore Francois; Val Pierre; Sahut Barnola Isabelle; Ragazzon Bruno; Louiset Estelle; Delarue Catherine; Lefebvre Herve; Urade Yoshihiro; Martinez Antoine

来源：PLos One, 2009, 4(10): e7309.

DOI：10.1371/journal.pone.0007309

Prostaglandin F-2 alpha (PGF(2 alpha)), represses ovarian steroidogenesis and initiates parturition in mammals but its impact on adrenal gland is unknown. Prostaglandins biosynthesis depends on the sequential action of upstream cyclooxygenases (COX) and terminal synthases but no PGF(2 alpha) synthases (PGFS) were functionally identified in mammalian cells. In vitro, the most efficient mammalian PGFS belong to aldo-keto reductase 1B (AKR1B) family. The adrenal gland is a major site of AKR1B expression in both human (AKR1B1) and mouse (AKR1B3, AKR1B7). Thus, we examined the PGF(2 alpha) biosynthetic pathway and its functional impact on both cortical and medullary zones. Both compartments produced PGF(2 alpha) but expressed different biosynthetic isozymes. In chromaffin cells, PGF(2 alpha) secretion appeared constitutive and correlated to continuous expression of COX1 and AKR1B3. In steroidogenic cells, PGF(2 alpha) secretion was stimulated by adrenocorticotropic hormone (ACTH) and correlated to ACTH-responsiveness of both COX2 and AKR1B7/B1. The pivotal role of AKR1B7 in ACTH-induced PGF(2 alpha) release and functional coupling with COX2 was demonstrated using over-and down-expression in cell lines. PGF(2 alpha) receptor was only detected in chromaffin cells, making medulla the primary target of PGF(2 alpha) action. By comparing PGF(2 alpha)-responsiveness of isolated cells and whole adrenal cultures, we demonstrated that PGF(2 alpha) repressed glucocorticoid secretion by an indirect mechanism involving a decrease in catecholamine release which in turn decreased adrenal steroidogenesis. PGF(2 alpha) may be regarded as a negative autocrine/paracrine regulator within a novel intra-adrenal feedback loop. The coordinated cell-specific regulation of COX2 and AKR1B7 ensures the generation of this stress-induced corticostatic signal.

• 出版日期2009-10-7