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

Abstract

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...

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