Urocortin-dependent effects on adrenal morphology, growth, and expression of steroidogenic enzymes in vivo

Abstract

Urocortin (UCN) 1, 2, and 3 are members of the corticotropin-releasing factor (CRF) family that display varying affinities to the CRF receptor 1 (CRFR1 (CRHR1)) and 2 (CRFR2 (CRHR2)). UCNs represent important modulators of stress responses and are involved in the control of anxiety and related disorders. In addition to the CNS, UCNs and CRFRs are highly expressed in several tissues including the adrenal gland, indicating the presence of UCN-dependent regulatory mechanisms in these peripheral organ systems. Using knockout (KO) mouse models lacking single or multiple Ucn genes, we examined the potential role of the three different Ucns on morphology and function of the adrenal gland. Adrenal morphology was investigated, organ size, cell size, and number were quantified, and growth kinetics were studied by proliferative cell nuclear antigen staining and Ccnd1 expression analysis. Furthermore, mRNA expression of enzymes involved in steroidogenesis and catecholamine synthesis was quantified by real-time PCR. Following this approach, Ucn2, Ucn1/Ucn2 dKO and Ucn1/Ucn2/Ucn3 tKO animals showed a significant cellular hypotrophy of the adrenal cortex and an increase in Ccnd1 expression, whereas in all other genotypes, no changes were observable in comparison to age-matched controls. For steroidogenesis, Ucn2/Ucn3 dKO animals displayed the most pronounced changes, with significant increases in all investigated enzymes, providing indirect evidence for increased stress behavior. Taken together, these data suggest that mainly Ucn2 and Ucn3 could be involved in adrenal stress response regulation while Ucn2 additionally appears to play a role in morphology and growth of the adrenal gland.

Stress‐induced changes in gene expression of urocortin 2 and other CRH peptides in rat adrenal medulla: involvement of glucocorticoids

“…In this regard, studies in knockout animals showed a limited effect of Ucn3 deficiency, as compared to Ucn2 deficiency, on adrenal function and growth (Riester et al . ).…”

“…Furthermore, in Ucn2 KO mice mRNA levels of adrenomedullary TH and phenylethanolamine N‐methyltransferase are significantly decreased compared to WT mice (Riester et al . ). However, depending on the dose and duration of treatment, Ucn2 can also act as an inhibitory factor on the catecholaminergic system (Dermitzaki et al .…”

“…Treatment of PC12 cells with Ucn2 stimulates NE secretion, induces phosphorylation of tyrosine hydroxylase (TH) , and elevates TH mRNA and protein levels ). Furthermore, in Ucn2 KO mice mRNA levels of adrenomedullary TH and phenylethanolamine N-methyltransferase are significantly decreased compared to WT mice (Riester et al 2012). However, depending on the dose and duration of treatment, Ucn2 can also act as an inhibitory factor on the catecholaminergic system ).…”

“…An absence of Ucn3 mRNA has also been demonstrated by in situ hybridization in human adrenal medulla . In this regard, studies in knockout animals showed a limited effect of Ucn3 deficiency, as compared to Ucn2 deficiency, on adrenal function and growth (Riester et al 2012).…”

The effects of neuropeptide urocortin 2 on the spontaneous discharge and glutamatergic neurotransmission of striatum neurons

“…CRFR1 had a strong affinity for CRF and UCN1 peptides while UCN2 and UCN3 only showed specific binding property to CRF-R2 in rats (Nemoto et al, 2007). UCN was similar to CRF in biological activity and, through the hypothalamus-adenohypophysis-adrenal axis, it could promote the adenohypophysis adrenal cortical hormone secretion (Riester et al, 2012). UCN not only regulated emergency response and stress in the peripheral tissues, but also participated in some functional changes in the central nervous system, including the modulation of appetite, intension, worry and anxiety, the inhibition of scald edema and the regulation of electrolyte and water balances.…”