Overlapping nongenomic and genomic actions of thyroid hormone and steroids

Davis, Paul J.; Lin, Hung Yun; Mousa, Shaker A.; Luidens, Mary K.; Hercbergs, Aleck; Wehling, Martin; Davis, Faith B.

doi:10.1016/j.steroids.2011.02.012

Cited by 37 publications

(37 citation statements)

References 98 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The hormone-receptor complex then binds to the androgen response elements, either inducing or suppressing the androgen-responsive genes (8), which is considered the genomic effect. In addition, androgens can also display an acute, receptor-dependent or independent effect by a nongenomic pathway, which has been observed in rat osteoblasts, luteinizing cells in human granulose, Sertoli cells, brain, and especially in vasculature (12,13). In vasculature, the rapid vasodilator effect of testosterone cannot be attenuated by pretreatment with the AR blocker flutamide.…”

Section: Discussionmentioning

confidence: 98%

Testosterone enhances tubuloglomerular feedback by increasing superoxide production in the macula densa

Liu

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

Males have higher prevalence of hypertension and renal injury than females, which may be attributed in part to androgen-mediated effects on renal hemodynamics. Tubuloglomerular feedback (TGF) is an important mechanism in control of renal microcirculation. The present study examines the role of testosterone in the regulation of TGF responses. TGF was measured by micropuncture (change of stop-flow pressure, ⌬P sf) in castrated Sprague-Dawley rats. The addition of testosterone (10 Ϫ7 mol/l) into the lumen increased the ⌬P sf from 10.1 Ϯ 1.2 to 12.2 Ϯ 1.2 mmHg. To determine whether androgen receptors (AR) are involved, mRNA of AR was measured in the macula dense cells isolated by laser capture microdissection from kidneys, and a macula densa-like cell line (MMDD1). AR mRNA was expressed in the macula densa of rats and in MMDD1 cells. We next examined the effects of the AR blocker, flutamide (10 Ϫ5 mol/l) on the TGF response. The addition of flutamide blocked the effects of testosterone on TGF. The addition of Tempol (10 Ϫ4 mol/l) or polyethylene glycol-superoxide dismutase (100 U/ml) to scavenge superoxide blocked the effect of testosterone to augment TGF. We then applied apocynin to inhibit NAD(P)H oxidase and oxypurinol to inhibit xanthine oxidase and found the testosterone-induced augmentation of TGF was blocked. In additional experiments in MMDD1 cells, we found that testosterone increased O 2 Ϫ generation. Apocynin or oxypurinol blocked the testosteroneinduced increases of O 2 Ϫ , while blockade of COX-2 with NS-398 had no effect. These findings suggest that testosterone enhances TGF response by stimulating O 2 Ϫ production in macula densa via an AR-dependent pathway.superoxide; testosterone; tubuloglomerular feedback THE KIDNEY PLAYS A CENTRAL role in long-term control of blood pressure. Tubuloglomerular feedback (TGF) is an important mechanism of the kidney in control of renal hemodynamics and salt and water balance. TGF is a negative feedback loop that senses changes in the delivery of NaCl to the macula densa (MD) and adjusts the tone of the afferent arteriole. Increases of luminal NaCl concentration activate TGF, which constricts the afferent arteriole and reduces single-nephron glomerular filtration rate. Together with other renal mechanisms that modulate salt and water balance, TGF controls the amount of NaCl delivery to the distal nephron and prevents excess salt excretion (31,43,49).Enhanced TGF responses have been reported in several models of hypertension, including spontaneous hypertensive rats (SHR) (5), Goldblatt hypertension (22, 35), and hypertensive ren-2 transgenic rats (27). These studies indicate that enhanced TGF responsiveness may contribute to the development of hypertension. There are also important sex differences in the severity of hypertension in these models, suggesting an important modulatory role of sex hormones. Hypertension is far more prevalent in men than in premenopausal women (38). After menopause, the incidence of hypertension in females rises to the same or even higher leve...

show abstract

Section: Discussionmentioning

confidence: 98%

Testosterone enhances tubuloglomerular feedback by increasing superoxide production in the macula densa

Liu

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

show abstract

“…There are several lines of evidence showing the integrated actions of T 3 and E 2 in models of tumors (13), reproduction, and sexual behavior (17,58). Because we performed in vivo experiments, it was impossible to be certain that E 2 and T 3 interact in renal tissue to regulate the expression of this enzyme.…”

Section: E791mentioning

confidence: 98%

“…Similarly to TH (13), sex steroids (32) also demonstrate nongenomic action (12). Presently, there is a growing body of evidence showing cross-talk between TH and estradiol activity, both genomic and nongenomic, in breast tumor, thyroid, and neural cell lines (13).…”

mentioning

confidence: 99%

Thyroid hormone and estradiol have overlapping effects on kidney glutathioneS-transferase-α gene expression

Faustino

Almeida

Pereira

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

Class GST (Gsta) represents an essential component of cellular antioxidant defense mechanisms in both the liver and the kidney. Estrogens and thyroid hormones (TH) play central roles in animal development, physiology, and behavior. Evidence of the overlapping functions of thyroid hormones and estrogens has been shown, although the molecular mechanisms are not always clear. We evaluated an interaction between TH and estradiol in regulating kidney Gsta expression and function. First, we observed that female mice expressed greater amounts of Gsta compared with males and showed an opposite pattern of expression in TR␤ knock-in mice. To further investigate these sex differences, hypothyroidism was induced by a 5-propyl-2-thiouracil diet, and hyperthyroidism was induced by daily T 3 injections. Hypothyroidism increased kidney Gsta expression in male mice but not in female mice, indicating that sex hormones could be influencing the regulation of Gsta by thyroid hormones. To analyze this hypothesis, ovariectomized females were subjected to hypo-and hyperthyroidism, which led to a male profile of Gsta expression. When hypo-or hyperthyroid ovariectomized mice were treated with 17␤-estradiol benzoate, we were able to confirm that estradiol was interfering with TH modulation; Gsta expression is increased by T 3 when estradiol is present and decreased by T 3 when estradiol is absent. Using proximal tubule cells, we also showed that estradiol and T 3 worked together to modulate Gsta expression in an overlapping fashion. In summary, 1) the sex difference in the basal expression of Gsta impacts the detoxification process, 2) kidney Gsta expression is regulated by TH in males and females but in opposite directions, and 3) T 3 and estradiol interact directly in renal proximal cells to regulate Gsta expression in females.triiodothyronine; proximal tubule; cross-talk; ovariectomy; estrogen GLUTATHIONE S-TRANSFERASES (GSTs) are a superfamily of ubiquitous dimeric detoxification isoenzymes that conjugate many substrates to reduced glutathione (GSH), including several xenobiotic and endogenous electrophiles (26). Mammalian cytosolic GSTs represent the largest family of such transferases and have been divided into seven different classes (␣, , , , , , and ) (2, 27, 28). The ␣-class of GST (GST␣) is found in several organs, such as the liver, kidney, lung, stomach, and gonads, some of which exhibit sexual dimorphism (35). In the liver, the important role played by GST in cellular detoxification and in many other known functions has already been well described (26). However, in other tissues, the role of GST is still not well characterized.It has been established that GST␣ is a biomarker of renal toxicity that aids in the detoxification of endogenous and exogenous compounds and in drug metabolism (2). Renal GST isoforms are differentially expressed along nephron segments; expression also depends on species. In the human kidney, GST␣ is found predominantly in the proximal convoluted tubule, and low levels of GST␣ have been detected in the...

show abstract

“…These receptors act by binding specific DNA sequences called estrogen response elements (EREs) and thyroid response elements (TREs) within the regulatory regions of target genes [4,5] . Evidence of cross-talk between TH and E2 has been reported in past decades [6] in different experimental systems such as kidney [7] , neural [8,9] , thyroid [10] , and breast tumor [11][12][13] cell lines.…”

Section: Introductionmentioning

confidence: 99%

Impact of Thyroid Hormones on Estrogen Receptor α-Dependent Transcriptional Mechanisms in Ventromedial Hypothalamus and Preoptic Area

Faustino¹,

Gagnidze²,

Ortiga-Carvalho³

et al. 2015

Neuroendocrinology

View full text Add to dashboard Cite

Elevated levels of thyroid hormones (TH) reduce estradiol (E2)-dependent female sexual behavior. E2 stimulates progesterone receptor (Pgr) and oxytocin receptor (Oxtr) within the ventromedial hypothalamus and preoptic area, critical hypothalamic nuclei for sexual and maternal behavior, respectively. Here, we investigated the impact of TH on E2-dependent transcriptional mechanisms in female mice. First, we observed that triiodothyronine (T₃) inhibited the E2 induction of Pgr and Oxtr. We hypothesized that differences in histone modifications and receptor recruitment could explain the influence of TH on E2-responsive Pgr and Oxtr expression. We observed that histone H3 acetylation (H3Ac) and methylation (H3K4me3) was gene and brain-region specific. We then analyzed the recruitment of estrogen receptor α (ERα) and TH receptor α (TRα) on the putative regulatory sequences of Pgr and Oxtr. Interestingly, T₃ inhibited E2-induced ERα binding to a specific Pgr enhancer site, whereas TRα binding was not affected, corroborating our theory that the competitive binding of TRα to an ERα binding site can inhibit ERα transactivation and the subsequent E2-responsive gene expression. On the Oxtr promoter, E2 and T₃ worked together to modulate ERα and TRα binding. Finally, the E2-dependent induction of cofactors was reduced by hypothyroidism and T₃. Thus, we determined that the Pgr and Oxtr promoter regions are responsive to E2 and that T₃ interferes with the E2 regulation of Pgr and Oxtr expression by altering the recruitment of receptors to DNA and changing the availability of cofactors. Collectively, our findings provide insights into molecular mechanisms of response to E2 and TH interactions controlling sex behavior in the hypothalamus.

show abstract

Overlapping nongenomic and genomic actions of thyroid hormone and steroids

Cited by 37 publications

References 98 publications

Testosterone enhances tubuloglomerular feedback by increasing superoxide production in the macula densa

Testosterone enhances tubuloglomerular feedback by increasing superoxide production in the macula densa

Thyroid hormone and estradiol have overlapping effects on kidney glutathioneS-transferase-α gene expression

Impact of Thyroid Hormones on Estrogen Receptor α-Dependent Transcriptional Mechanisms in Ventromedial Hypothalamus and Preoptic Area

Contact Info

Product

Resources

About