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...
Background/Aims: Thyroid hormone (TH) signalling is critical for heart function. The heart expresses thyroid hormone receptors (THRs); THRα1 and THRβ1. We aimed to investigate the regulation mechanisms of the THRβ isoform, its association with gene expression changes and implications for cardiac function. Methods: The experiments were performed using adult male mice expressing TRβΔ337T, which contains the Δ337T mutation of the human THRB gene and impairs ligand binding. Cardiac function and RNA expression were studied after hypo-or hyperthyroidism inductions. T3-induced cardiac hypertrophy was not observed in TRβΔ337T mice, showing the fundamental role of THRβ in cardiac hypertrophy. Results: We identified a group of independently regulated THRβ genes, which includes Adrb2, Myh7 and Hcn2 that were normally regulated by T3 in the TRβΔ337T group. However, Adrb1, Myh6 and Atp2a2 were regulated via THRβ. The TRβΔ337T mice exhibited a contractile deficit, decreased ejection fraction and stroke volume, as assessed by echocardiography. In our model, miR-208a and miR-199a may contribute to THRβ-mediated cardiac hypertrophy, as indicated by the absence of T3-regulated ventricular expression in TRβΔ337T mice. Conclusion: THRβ has important role in the regulation of specific mRNA and miRNA in T3-induced cardiac hypertrophic growth and in the alteration of heart functions.
Triiodotironine (T3) is critical for cardiac function. Heart expresses TRα1 e TRβ1, the two main thyroid hormone (TH) receptors (TR). We aimed to investigate the role of TRβ1 on T3‐induced cardiac hypertrophy.Adult male mice, wild‐type (WT) or homozygous (HO) for Δ337T mutation on TRβ (unable to bind T3), were used. Animals were studied at baseline, after hypo‐ (PTU) and hyperthyroidism (PTU+T3) induction. Echo‐ and electrocardiogram were performed. Hearts were collected, weighed and total RNA was extracted. Expression of mRNA and miRNAs were quantified by real time RT‐PCR.T3 caused cardiac hypertrophy in WT, but not in HO animals when evaluated by cardiac index (P<0.001) or by echocardiography (25%, P<0.05). Genes responsive to T3 as ARb1, SERCa2 and HCN2 were responsive to T3 in WT but not in HO. Absence of a functional TRβ1 altered several parameters in HO cardiac function. Stroke volume and ejection fraction dropped in HO‐PTU+T3 vs. HO‐PTU. P wave reduced (50%, P<0.001) and heart rate increased (P<0.05) on WT‐PTU+T3 vs. WT‐PTU; but not in HO. Analysis of MicroRNAs miR‐1 and miR‐208, involved in cardiac hypertrophy, showed that T3 treatment increased both (2 to 3 times) in a different fashion, being miR‐1 TRβ independent and miR‐208 TRβ dependent.TH‐induced cardiac hypertrophy is TRβ‐dependent and involves miR‐208, while the absence of T3 ligation on TRβ promotes a significant deterioration in cardiac function.
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