Endothelin-1 contributes to the sexual differences in renal damage in DOCA-salt rats

Montezano, Augusto C.; Callera, Gláucia E.; Mota, Ali; Fortes, Zuleica Bruno; Nigro, Dorothy; Carvalho, Maria Helena Catelli de; Zorn, Telma Maria Tenório; Tostes, Rita C.

doi:10.1016/j.peptides.2005.03.038

Cited by 23 publications

(16 citation statements)

References 23 publications

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“…Consequently, aldosterone induction of edn1 may represent an important negative feedback loop on aldosterone-stimulated sodium reabsorption in the collecting duct. Indeed, the renal ET-1 pathway is differentially regulated in animals with mineralocorticoid-induced hypertension (62)(63)(64)(65)(66). However, direct support for this concept comes from studies conducted on collecting duct cell-specific edn1 knock-out mice.…”

Section: Discussionmentioning

confidence: 99%

Aldosterone Modulates Steroid Receptor Binding to the Endothelin-1 Gene (edn1)

Stow

Gumz

Lynch

et al. 2009

Journal of Biological Chemistry

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Aldosterone and endothelin-1 (ET-1) act on collecting duct cells of the kidney and are important regulators of renal sodium transport and cardiovascular physiology. We recently identified the ET-1 gene (edn1) as a novel aldosterone-induced transcript. However, aldosterone action on edn1 has not been characterized at the present time. In this report, we show that aldosterone stimulated edn1 mRNA in acutely isolated rat inner medullary collecting duct cells ex vivo and ET-1 peptide in rat inner medulla in vivo. Aldosterone induction of edn1 mRNA occurred in cortical, outer medullary, and inner medullary collecting duct cells in vitro. Inspection of the edn1 promoter revealed two putative hormone response elements. Levels of heterogeneous nuclear RNA synthesis demonstrated that edn1 mRNA stimulation occurred at the level of transcription. RNA knockdowns corroborated pharmacological studies and demonstrated both mineralocorticoid receptor and glucocorticoid receptor participated in this response. Aldosterone resulted in dose-dependent nuclear translocation and binding of mineralocorticoid receptor and glucocorticoid receptor to the edn1 hormone response elements. Hormone receptors mediated the association of chromatin remodeling complexes, histone modification, and RNA polymerase II at the edn1 promoter. Direct interaction between aldosterone and ET-1 has important implications for renal and cardiovascular function.The steroid hormone aldosterone is critical for sodium homeostasis and blood pressure control. Aldosterone works by modulating the fine regulation of sodium reabsorption in the distal nephron and collecting duct of the kidney. Classic aldosterone action is mediated through the mineralocorticoid receptor (MR), 3 a member of the nuclear receptor family of proteins that function as ligand-dependent transcription factors (1). MR acts on cells of the distal nephron and collecting duct to stimulate transcription of genes involved in transepithelial sodium transport, including the epithelial sodium channel ␣ subunit (scnn1a, ␣ENaC), the sodium, potassium-ATPase ␣1 subunit (atp1a1), and the serum-and glucocorticoid-regulated kinase-1 (sgk1) (2). The increase in expression of genes involved in sodium transport results in net sodium reabsorption followed by in increase in extracellular fluid volume and a consequent increase in blood pressure. Indeed, MR antagonists such as spironolactone and eplerenone are used clinically as diuretic and anti-hypertensive agents (3). The mechanism of MR action is consistent with a classic steroid receptor mechanism (4). Prior to activation MR resides in the cytosol. Ligand binding induces a conformational change that releases chaperone proteins and reveals a nuclear localization signal. Nuclear MR binds directly to DNA at hormone response elements (HREs) in target genes to modulate their transcription. A typical HRE for MR consists of two receptor binding half-sites with the consensus sequence 5Ј-TGTTCT-3Ј, arranged as an inverted palindrome (1, 5). These HREs facilitate binding of...

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Section: Discussionmentioning

confidence: 99%

Aldosterone Modulates Steroid Receptor Binding to the Endothelin-1 Gene (edn1)

Stow

Gumz

Lynch

et al. 2009

Journal of Biological Chemistry

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“…Similarly, in a rat model of DOCA-salt hypertension, ovariectomy worsened ET-1-mediated vasoconstriction, which could be reversed by supplementation with exogenous estrogen with or without progesterone (24). ET-1 levels were increased in both male and female ovariectomized DOCA-salt hypertensive rats with improvements in blood pressure and consequent renal lesions on treatment with either hormone replacement therapy (females only) or ET A receptor blockers (66). Further evidence of a protective effect of estrogen on ET-1-mediated vascular pathologies is shown in a rat model of trauma hem- Fig.…”

Section: Sex Hormones and Endothelinmentioning

confidence: 92%

Endothelin in the female vasculature: a role in aging?

Lekontseva

Chakrabarti

Davidge

2010

American Journal of Physiology-Regulatory, Integrative and Comp

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vascular diseases are the leading cause of morbidity and mortality in the world. Aging is associated with an increased incidence of cardiovascular disease. Premenopausal women are relatively protected from vascular alterations compared with age-matched men, likely due to higher levels of the female sex hormones. However, these vasoprotective effects in women are attenuated after menopause. Thus, the vascular system in aging women is affected by both the aging process as well as loss of hormonal protection, positioning women of this age group at a high risk for cardiovascular diseases such as hypertension, myocardial infarction, and stroke. The endothelin system in general and endothelin-1 (ET-1) in particular plays an important role in the pathogenesis of vascular dysfunction associated with aging. Evidence suggests that the female sex steroids can interfere with the vascular expression and actions of ET-1 via several mechanisms, which may further contribute to pathological processes in the vasculature of aging women. In this review, we have summarized hormone-dependent vascular pathways whereby ET-1 may mediate the deleterious effects of aging in postmenopausal females.ET-1; menopause; estrogen; vasoconstriction; inflammation AGING OF THE VASCULAR SYSTEM is a complex process characterized by sustained proinflammatory and proconstrictor changes in the vascular microenvironment. The resulting structural and functional alterations in systemic vasculature lead to increased risk of cardiovascular diseases such as hypertension, myocardial infarction, and stroke in the aging population (12,18,51,70). In the absence of chronic preexisting conditions, such as diabetes, premenopausal women express a favorable cardiovascular phenotype compared with age-matched men, largely due to the vasoprotective role of ovarian steroids such as estrogen (92). An alteration in circulating sex hormones at menopause, such as the decrease in estrogens and a relative excess of androgens, is associated with the conversion from a low-to high-risk cardiovascular profile (19,56). Although the mechanisms underlying the pathogenesis of vascular dysfunction in postmenopausal women are not completely understood, it is believed to result from a complex interplay between the aging process and the decline in ovarian hormones like estrogen.Endothelin has emerged as one of the key mediators of vascular dysfunction and remodeling in aging. Interestingly, there is evidence that female sex steroids (in particular, estrogen) can regulate the endothelin system at various levels from gene transcription and posttranslational modification of the peptide to expression of its vascular receptors and postreceptor signaling events. This review will summarize current knowledge on the impact of aging and female sex hormones on the endothelin system, as well as outline directions where further research is needed. A better understanding of the role of endothelin in the pathogenesis of vascular dysfunction in postmenopausal women may lead to the development of novel sex-...

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“…These findings are tempered somewhat by the finding of Kausz et al who reports that women in the United States tend to start dialysis at lower level of residual renal function than men (21). Exploration for the biological basis of gender differences has identified potential estrogensensitive pathways in inflammatory, vascular, and mesangial responses to renal injury (22)(23)(24)(25)(26).…”

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confidence: 99%

Effects of flaxseed derivatives in experimental polycystic kidney disease vary with animal gender

Ogborn

Nitschmann

Bankovic-Calic

et al. 2006

Lipids

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Flaxseed derivatives, including both oil and flax lignan, modify progression of renal injury in animal models, including Han:SPRD-cy polycystic kidney disease (PKD). Gender is a significant factor in the rates of progression of many forms of human renal disease, but the role of gender in the response to nutrition intervention in renal disease is unexplored. In this study, male and female Han:SPRD-cy rats or normal littermates were fed either corn oil (CO) or flax oil (FO) diets, with or without 20 mg/kg of the diet flax lignan secoisolaricinoresinol dyglycoside (SDG). Renal injury was assessed morphometrically and biochemically. Renal and hepatic PUFA composition was assessed by GC and renal PGE2 release by ELISA. FO preserved body weight in PKD males, with no effect in females. SDG reduced weight in both normal and PKD females. FO reduced proteinuria in both male and female PKD. FO reduced cystic change and renal inflammation in PKD males but reduced cystic change, fibrosis, renal inflammation, tissue lipid peroxides, and epithelial proliferation in PKD females. SDG reduced renal inflammation in all animals and lipid peroxides in PKD females. A strong interaction between SDG and FO was observed in renal FA composition of female kidneys only, suggesting increased conversion of C18 PUFA to C20 PUFA. FO reduced renal release of PGE2 in both genders. Gender influences the effects of flaxseed derivatives in Han:SPRD-cy rats. Gender-based responses to environmental factors, such as dietary lipid sources and micronutrients, may contribute to gender-based differences in disease progression rates.

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Endothelin-1 contributes to the sexual differences in renal damage in DOCA-salt rats

Cited by 23 publications

References 23 publications

Aldosterone Modulates Steroid Receptor Binding to the Endothelin-1 Gene (edn1)

Aldosterone Modulates Steroid Receptor Binding to the Endothelin-1 Gene (edn1)

Endothelin in the female vasculature: a role in aging?

Effects of flaxseed derivatives in experimental polycystic kidney disease vary with animal gender

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