Disabled-2 Is Expressed in Adrenal Zona Glomerulosa and Is Involved in Aldosterone Secretion

Romero, Damián G.; Yanes, Licy L.; Rodriguez, Angela F. de; Plonczynski, Maria W.; Welsh, Bronwyn L.; Reckelhoff, Jane F.; Gómez-Sánchez, Elise P.; Gómez-Sánchez, Celso E.

doi:10.1210/en.2006-1509

Cited by 63 publications

(62 citation statements)

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“…For example, the adrenal glands and ovaries of humans use LDL-derived cholesterol to produce steroid hormones (42)(43)(44). Nitric oxide inhibits steroid production ( 45 ), and the high levels of dab2 expressed in steroidogenic tissues ( 46,47 ) may facilitate LDL uptake when nitric oxide levels are low and cholesterol demand for steroid production is high. More generally, activation of ERK induces LDLR expression in dividing cells to supply the cholesterol needed for membrane biogenesis ( 48 ).…”

Section: Discussionmentioning

confidence: 99%

S-nitrosylation of ARH is required for LDL uptake by the LDL receptor

Zhao

Pompey

Dong

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org (ARH) and the disabled-like protein 2 (dab2). Both ARH and dab2 target LDLRs to coated pits through binding sites for the LDLR, clathrin, and the adaptor protein 2 (AP-2) complex. ARH binds to the FDNPVY 807 sequence of the LDLR through a phosphotyrosine-binding (PTB) domain, to the heavy chain of clathrin through a clathrin box sequence, and to the ␤ 2-subunit of AP-2 through a sequence with strong homology to the AP-2-binding sequences of ␤ -arrestins ( 5-8 ) ( Fig. 1A ). Y807 of the FDNPVY 807 plays a critical role in the interaction of ARH and dab2 with the LDLR, and mutation of Y807 to either cysteine or alanine cripples LDLR-dependent LDL uptake ( 3,5,8,9 ). By contrast, uptake of VLDL remnants does not require ARH, dab2, or a functional FDNPVY sequence because binding of VLDL remnants to the LDLR induces a separate endocytic process that involves a second internalization motif on the LDLR cytoplasmic domain ( 10 ). It is not clear why the LDLR needs an induced process for VLDL remnant uptake when the FDNPVY-dependent process can internalize both LDL and VLDL remnants, nor why the FDNPVY process utilizes both the ARH and dab2 adaptors when either adaptor is suffi cient to support lipoprotein uptake by the LDLR.A key question is why an ARH is necessary. ARH has highest expression in kidney, liver, and placenta ( 11 ); however, dab2 is also highly expressed in both kidney and placenta, and it is dab2, not ARH, that is required for normal placental and kidney function ( 12 ). Hepatocytes and peripheral blood leukocytes lack dab2 ( 13,14 ), and ARH defi ciency in both humans and mice sharply reduces LDL clearance rates, resulting in hypercholesterolemia ( 15-18 ). Why hepatocytes and leukocytes normally rely upon ARH is unclear because both cell types lose their dependence on ARH for LDL uptake when dab2 expression is induced Abstract The LDL receptor (LDLR) relies upon endocytic adaptor proteins for internalization of lipoproteins. The results of this study show that the LDLR adaptor autosomal recessive hypercholesterolemia protein (ARH) requires nitric oxide to support LDL uptake. Nitric oxide nitrosylates ARH at C199 and C286, and these posttranslational modifi cations are necessary for association of ARH with the adaptor protein 2 (AP-2) component of clathrin-coated pits. In the absence of nitrosylation, ARH is unable to target LDL-LDLR complexes to coated pits, resulting in poor LDL uptake. The role of nitric oxide on LDLR function is specifi c for ARH because inhibition of nitric oxide synthase activity impairs ARH-supported LDL uptake but has no effect on other LDLR-dependent lipoprotein uptake processes, including VLDL remnant uptake and dab2-supported LDL uptake. These fi ndings suggest that cells that depend upon ARH for LDL uptake can control which lipoproteins are internalized by their LDLRs through changes in nitric oxide. -Zhao, Z., S. Pompey, H. Dong, J. Weng, R. Garuti, and P. Michaely. The LDL receptor (LDLR) internalizes a broad spectrum ...

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Section: Discussionmentioning

confidence: 99%

S-nitrosylation of ARH is required for LDL uptake by the LDL receptor

Zhao

Pompey

Dong

et al. 2013

Journal of Lipid Research

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“…Whereas peritumoral ZG express both isoforms, APA express almost exclusively HSD3B2 (Doi et al 2014); nevertheless, HSD3B2 mRNA is also expressed in cortisolproducing adenoma and in nonfunctioning adenoma (Sakuma et al 2013), making it unsuitable for diagnosis. Other specific markers of ZG have been described, such as disabled-2 (dab2), specifically expressed in the ZG (Romero et al 2007, Boulkroun et al 2010) and involved in aldosterone secretion (Romero et al 2007) and GIRK4 ; both are expressed in APA (Boulkroun et al 2010 making them the potential candidates to improve APA diagnosis.…”

Section: Familial Hyperaldosteronism Type IImentioning

confidence: 99%

An update on novel mechanisms of primary aldosteronism

Zennaro¹,

Boulkroun²,

Fernandes-Rosa³

2014

Journal of Endocrinology

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Primary aldosteronism (PA) is the most common and curable form of secondary hypertension. It is caused in the majority of cases by either unilateral aldosterone overproduction due to an aldosterone-producing adenoma (APA) or by bilateral adrenal hyperplasia. Recent advances in genome technology have allowed researchers to unravel part of the genetic abnormalities underlying the development of APA and familial hyperaldosteronism. Recurrent somatic mutations in genes coding for ion channels (KCNJ5 and CACNA1D) and ATPases (ATP1A1 and ATP2B3) regulating intracellular ionic homeostasis and cell membrane potential have been identified in APA. Similar germline mutations of KCNJ5 were identified in a severe familial form of PA, familial hyperaldosteronism type 3 (FH3), whereas de novo germline CACNA1D mutations were found in two cases of hyperaldosteronism associated with a complex neurological disorder. These results have allowed a pathophysiological model of APA development to be established. This model involves modifications in intracellular ionic homeostasis and membrane potential, accounting for w50% of all tumors, associated with specific gender differences and severity of PA. In this review, we describe the different genetic abnormalities associated with PA and discuss the mechanisms whereby they lead to increased aldosterone production and cell proliferation. We also address some of the foreseeable consequences that genetic knowledge may contribute to improve diagnosis and patient care.

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“…To characterize more precisely the cellular composition of areas expressing CYP11B2, we investigated expression of CYP11B2, CYP11B1, and Dab2 (disabled 2, a specific marker of the ZG in rodent 13 ) in 15 control adrenals. We considered that this large number could give a reliable estimate of CYP11B2 expression if considering variables possibly affecting aldosterone biosynthesis, including sex, age, salt intake, anesthesia, and medication.…”

Section: Functional Zonation Of the Human Zg Differs From Rodentsmentioning

confidence: 99%

“…To further investigate the cellular phenotype of aldosterone-producing cells in normal adrenal glands and PAL and to explore the nature of APCCs, we have analyzed the expression of CYP11B2 in relation to specific markers of ZG (disabled 2 13 ) and ZF/reticularis (CYP11B1). Furthermore, we investigated the morphology, nodulation, and vascularization of the perinodular adrenal cortex and correlated these findings with CYP11B2 expression.…”

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confidence: 99%

Adrenal Cortex Remodeling and Functional Zona Glomerulosa Hyperplasia in Primary Aldosteronism

et al. 2010

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Abstract-Primary aldosteronism is the most common form of secondary hypertension with hypokalemia and suppressed renin-angiotensin system caused by autonomous aldosterone production. Our aim was to compare zona glomerulosa (ZG) structure and function between control adrenals and the peritumoral tissue from patients operated on for aldosterone-producing adenoma. ZG morphology and CYP11B1, CYP11B2, and disabled 2 expression were studied in 15 control adrenals and 25 adrenals with aldosterone-producing adenoma. A transcriptome analysis was done using publicly available data sets. In control adrenals, ZG was discontinuous, and CYP11B2 expression was focal or partly continuous and localized to 3 structures, foci, megafoci, and aldosterone-producing cell clusters. CYP11B2 expression was restricted to a limited number of ZG cells expressing Dab2 but not CYP11B1; aldosterone-producing cell clusters were composed of cells with an intermediate phenotype expressing CYP11B2 but not disabled 2 or CYP11B1. In peritumoral tissue, large remodeling of the adrenal cortex was observed with increased nodulation and decreased vascularization that were not correlated with CYP11B2 expression. In 17 out of 25 adrenals, hyperplasia of adjacent ZG was observed with persistent expression of CYP11B2 that was extended to the entire ZG. In all of the adrenals from patients with aldosterone-producing adenoma, CYP11B2 expression was present in foci, megafoci, and aldosteroneproducing cell clusters. Transcriptome profiling indicates a close relationship between peritumoral and control adrenal cortex. In conclusion, adrenal cortex remodeling, reduced vascularization, and ZG hyperplasia are major features of adrenals with aldosterone-producing adenoma. Transcriptional phenotyping is not in favor of this being an intermediate step toward the formation of aldosterone-producing adenoma. (Hypertension. 2010;56:885-892.)Key Words: zona glomerulosa hyperplasia Ⅲ aldosterone-producing adenoma Ⅲ secondary hypertension Ⅲ adrenal cortex remodeling Ⅲ aldosterone Ⅲ potassium Ⅲ transcriptome P rimary aldosteronism (PAL) is the most common form of endocrine hypertension with a prevalence of 7% to 10% of hypertensive patients. 1 In PAL, autonomous production of aldosterone is associated with suppressed renin activity, hypokalemia, and hypertension. The two principal forms are unilateral aldosterone-producing adenoma (APA), a benign tumor of the adrenal cortex, and bilateral adrenal hyperplasia, also known as idiopathic hyperaldosteronism. Whereas in APA the adjacent zona glomerulosa (ZG) is believed to be nonfunctional because of negative feedback regulation, bilateral adrenal hyperplasia involves the entire ZG of both adrenal glands. 2 Patients with PAL operated on the basis of an APA, and/or a lateralized aldosterone hypersecretion can be cured by unilateral adrenalectomy. However, only Ϸ70% of patients with lateralized aldosterone secretion are cured by surgery, 3 suggesting that, in some cases, residual aldosterone secretion from the contralateral adrenal g...

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Disabled-2 Is Expressed in Adrenal Zona Glomerulosa and Is Involved in Aldosterone Secretion

Cited by 63 publications

References 62 publications

S-nitrosylation of ARH is required for LDL uptake by the LDL receptor

S-nitrosylation of ARH is required for LDL uptake by the LDL receptor

An update on novel mechanisms of primary aldosteronism

Adrenal Cortex Remodeling and Functional Zona Glomerulosa Hyperplasia in Primary Aldosteronism

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