Urocortin 1, Urocortin 3/Stresscopin, and Corticotropin-Releasing Factor Receptors in Human Adrenal and Its Disorders

Fukuda, Tsuyoshi; Takahashi, Kazuhiro; Suzuki, Takashi; Saruta, Masayuki; Watanabe, Mika; Nakata, Taisuke; Sasano, Hironobu

doi:10.1210/jc.2005-0090

Cited by 43 publications

(38 citation statements)

References 51 publications

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“…A possible model of indirect or direct interaction between the adrenal cortex and the medulla has been proposed, for example, by Fukuda et al (2005). Comparable to this phenotype is the Crfr1/2 KO model described previously, where an atrophy of the zona fasciculata and a phenotype of glucocorticoid insufficiency could be documented (Preil et al 2001).…”

Section: Discussionmentioning

confidence: 99%

“…However, stimulation of specific CRFRs in distinct tissues or cell types by receptor-selective CRF peptides has been demonstrated to activate a variety of further signaling pathways (Brar et al 2002, Bale 2005. UCN1 has similar binding affinity to CRFR1 and CRFR2 while UCN2 and UCN3 are considered as specific ligands for CRFR2 (Fukuda et al 2005). These specific binding properties translate into distinct phenotypic changes induced by targeted deletions of the CRF receptors.…”

Section: Introductionmentioning

confidence: 99%

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

Riester

Spyroglou²,

Neufeld-Cohen³

et al. 2012

Journal of Molecular Endocrinology

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Riester

Spyroglou²,

Neufeld-Cohen³

et al. 2012

Journal of Molecular Endocrinology

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“…As we know, the main endogenous CRF peptide is Ucn. However, usage of Ucn does not help to determine the functioning receptor type as Ucn binds with both receptors equally (Vaughan et al 1995, Fukuda et al 2005. Therefore, to investigate concrete roles of the two receptors, CRF (R1 agonist) and Ucn2 (R2 agonist) were used instead of Ucn.…”

Section: Discussionmentioning

confidence: 99%

Different effects of corticotropin-releasing factor and urocortin 2 on apoptosis of prostate cancer cells in vitro

Jin¹,

Zhang²,

Guo³

et al. 2011

Journal of Molecular Endocrinology

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Urocortin (Ucn), a corticotropin-releasing factor (CRF)-related neuropeptide binding both CRF type 1 receptor (CRFR1) and CRFR2, has recently been found in prostate cancer. However, no report has yet been known to elucidate the roles of Ucn in prostate cancer via the two receptors. In this study, the expression of both CRFR1 and CRFR2 in the mouse prostate cancer cell line RM-1 were detected and cellular apoptosis was monitored in the presence of CRF or Ucn2, the CRFR1-and CRFR2-selective agonist respectively. CRF promoted apoptosis while Ucn2 exerted the opposite effect. CRF reduced Bcl-2 expression, induced Bax expression, and hyperpolarized the mitochondrial membrane potential to activate caspase-9. On the contrary, Ucn2 increased Bcl-2 expression and decreased Bax expression, in which phosphorylation of Akt and cyclic AMP response element-binding (CREB) was involved. Pretreatment with phosphatidylinositide 3-kinase/Akt inhibitor (LY-294002) prior to Ucn2 led to downregulation of CREB phosphorylation and hence reduced Bcl-2 expression. These effects of CRF and Ucn2 were abolished by antalarmin (Anta) and antisauvagine-30, the CRFR1-and CRFR2-selective antagonist respectively. In LNCaP cell line, similar effects on cell apoptosis by CRF and Ucn2 were observed. In summary, our results demonstrated CRFR1 and CRFR2 expression in prostate cancer and indicated the opposite apoptotic roles of the two different CRFRs. These data may contribute to uncovering the pathophysiological function of endogenous Ucn in prostate tumorigenesis and progression.

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“…The trend for aldosterone levels to decline over this same period, where plasma ACTH and potassium were unchanged, might suggest a possible direct inhibitory effect of Ucn1 on the hormone's secretion, especially given the strong immunoreactivity of Ucn1 demonstrated in the medulla of the adrenal gland (13). Alternatively, possible Ucn1-induced reductions in serum angiotensin-converting enzyme activity (45) might explain the decline in aldosterone in the present study via decreased angiotensin II (a prime secretagogue for aldosterone in HF).…”

Section: Discussionmentioning

confidence: 83%

Urocortin 1 administration from onset of rapid left ventricular pacing represses progression to overt heart failure

Rademaker

Charles²,

Richards³

2007

American Journal of Physiology-Heart and Circulatory Physiology

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Rademaker MT, Charles CJ, Richards AM. Urocortin 1 administration from onset of rapid left ventricular pacing represses progression to overt heart failure. Am J Physiol Heart Circ Physiol 293: H1536-H1544, 2007. First published May 25, 2007; doi:10.1152/ajpheart.00377.2007.-Urocortin 1 (Ucn1) may be involved in the pathophysiology of heart failure (HF), but the impact of Ucn1 administration on progression of the disease is unknown. The aim of this study was to investigate the effects of Ucn1 in sheep from the onset of cardiac overload and during the subsequent development of HF. Eight sheep underwent two 4-day periods of HF induction by rapid left ventricular pacing (225 beats/min) in conjunction with continuous infusions of Ucn1 (0.1 g ⅐ kg Ϫ1 ⅐ h Ϫ1 iv) and a vehicle control (0.9% saline). Compared with control, Ucn1 attenuated the pacing-induced decline in cardiac output (2.43 Ϯ 0.46 vs. 3.70 Ϯ 0.89 l/min on day 4, P Ͻ 0.01) and increases in left atrial pressure (24.9 Ϯ 1.0 vs. 11.9 Ϯ 1.1 mmHg, P Ͻ 0.001) and peripheral resistance (38.7 Ϯ 9.4 vs. 25.2 Ϯ 6.1 mmHg ⅐ l Ϫ1 ⅐ min, P Ͻ 0.001). Ucn1 wholly prevented increases in plasma renin activity (4.02 Ϯ 1.17 vs. 0.87 Ϯ 0.1 nmol ⅐ l Ϫ1 ⅐ h Ϫ1 , P Ͻ 0.001), aldosterone (1,313 Ϯ 324 vs. 413 Ϯ 174 pmol/l, P Ͻ 0.001), endothelin-1 (3.8 Ϯ 0.5 vs. 2.0 Ϯ 0.1 pmol/l, P Ͻ 0.001), and vasopressin (10.8 Ϯ 4.1 vs. 1.8 Ϯ 0.2 pmol/l, P Ͻ 0.05) during pacing alone and blunted the progressive increases in plasma epinephrine (2,132 Ϯ 697 vs. 1,250 Ϯ 264 pmol/l, P Ͻ 0.05), norepinephrine (3.61 Ϯ 0.73 vs. 2.07 Ϯ 0.52 nmol/l, P Ͻ 0.05), and atrial (P Ͻ 0.05) and brain (P Ͻ 0.01) natriuretic peptide levels. Ucn1 administration also maintained urine sodium excretion (0.75 Ϯ 0.34 vs. 1.59 Ϯ 0.50 mmol/h on day 4, P Ͻ 0.05) and suppressed pacing-induced declines in creatinine clearance (P Ͻ 0.05). These findings indicate that Ucn1 treatment from the onset of cardiac overload has the ability to repress the ensuing hemodynamic and renal deterioration and concomitant adverse neurohumoral activation, thereby delaying the development of overt HF. These data strongly support a use for Ucn1 as a therapeutic option early in the course of the disease. cardiac output; hormones; renal function UROCORTIN 1 (Ucn1), a 40-amino acid peptide belonging to the corticotropin-releasing factor family (43), is reported to participate in regulation of the cardiovascular system. The peptide is present in high concentrations in the heart (24) and endothelial and smooth muscle cells of the systemic vasculature (12, 17), and its peripheral distribution closely matches that of the corticotropin-releasing factor receptor type 2, the G proteincoupled receptor reported to mediate its cardiovascular bioactivity (22,44). Systemic administration of Ucn1 induces sustained arterial (6,22,44) and venous (38) dilatation, increases in coronary blood flow and conductance, and positive inotropic and chronotropic effects (1,27,32,33,42). Ucn1 has also been shown to prevent cell death in cultured cardiac myocytes exposed to hyp...

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Urocortin 1, Urocortin 3/Stresscopin, and Corticotropin-Releasing Factor Receptors in Human Adrenal and Its Disorders

Abstract: Ucn1, Ucn3, and CRF receptors are all expressed in human adrenal cortex and medulla and may play important roles in physiological adrenal functions.

Cited by 43 publications

References 51 publications

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

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

Different effects of corticotropin-releasing factor and urocortin 2 on apoptosis of prostate cancer cells in vitro

Urocortin 1 administration from onset of rapid left ventricular pacing represses progression to overt heart failure

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