Expression of aromatase, androgen and estrogen receptors in peripheral target tissues in diabetes

Abstract

Our previous studies have shown that diabetes in the male streptozotocin (STZ)-induced diabetic rat is characterized by a decrease in circulating testosterone and concomitant increase in estradiol levels. Interestingly, this increase in estradiol levels persists even after castration, suggesting extra-testicular origins of estradiol in diabetes. The aim of the present study was to examine whether other target organs of diabetes may be sources of estradiol. The study was performed in male Sprague-Dawley non-diabetic (ND), STZ-induced diabetic (D) and STZ-induced diabetic castrated (Dcas) rats (n=8-9/group). 14 weeks of diabetes was associated with decreased testicular (ND, 26.3±4.19; D, 18.4±1.54; P<0.05), but increased renal (ND, 1.83±0.92; D, 7.85±1.38; P<0.05) and ocular (D, 23.4±3.66; D, 87.1±28.1; P<0.05) aromatase activity. This increase in renal (Dcas, 6.30±1.25) and ocular (Dcas, 62.7±11.9) aromatase activity persisted after castration. The diabetic kidney also had increased levels of tissue estrogen (ND, 0.31 ±0.01; D, 0.51±0.11; Dcas, 0.45±0.08) as well as estrogen receptor alpha protein expression (ND, 0.63±0.09; D, 1.62±0.28; Dcas, 1.38±0.20). These data suggest that in male STZ-induced diabetic rats, tissues other than the testis may become sources of estradiol. In particular, the diabetic kidney appears to produce estradiol following castration, a state that is associated with a high degree or renal injury. Overall, our data provides evidence for the extra-testicular source of estradiol that in males, through an intracrine mechanism, may contribute to the development and/or progression of end-organ damage associated with diabetes.

The estrogenic retina: The potential contribution to healthy aging and age-related neurodegenerative diseases of the retina

“…Salyer et al [37], showed expression of P450aro also in embryonic rat RPE, and a recent study reports aromatase also in the capillary of choroid of rats [54]. Our studies have proved E2 synthesis from aromatization of testosterone in a neurosteroidogenic pathway, via cholesterol, progesterone and/or testosterone metabolism [2,3,5].…”

“…In diabetes, E2 effects appear indeed to mediate opposite effects upon the tissue affected [54]. For instance, the elevated expression of aromatase and ERα in the kidney of men may contribute to the development and progression of renal disease, but the same elevation of the oestrogenic parameters in the retina and choroid capillaries may prevent retinopathy [54]. Neuroactive steroid levels (pregnenolone, progesterone and its metabolites, testosterone and its metabolites, and dehydroepiandrosterone) are decreased in several central and peripheral regions of the nervous system of diabetic rats, mostly in accordance with sex-and regional-specificity [141].…”

“…However, while E2 has been shown to counteract the reduced cell proliferation rate in the dentate gyrus and the abnormal expression of astrocytic markers in the hippocampus of diabetic rats [139], the oestrogen replacement therapy has elicited a deleterious, instead of protective, effect on the cerebral ischemia induced in diabetic ovariectomized rats [140]. In diabetes, E2 effects appear indeed to mediate opposite effects upon the tissue affected [54]. For instance, the elevated expression of aromatase and ERα in the kidney of men may contribute to the development and progression of renal disease, but the same elevation of the oestrogenic parameters in the retina and choroid capillaries may prevent retinopathy [54].…”

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

“…ARs are highly expressed in proximal tubule cells (8), cortical collecting ducts (4), afferent arterioles, glomerular endothelial cells, and podocytes (36). In target tissue, testosterone directly binds to the nuclear AR or converts to dihydrotestosterone, which binds the AR.…”

The Role of Sex Hormones in Diabetic Retinopathy

“…In addition, Rocha et al found the mRNA for 5 reductase, which translates the enzyme which converts testosterone to the more active DHT in the RPE . Prabhu et al found AR protein in all layers of rat retina except the ganglion and outer nuclear layers (Prabhu et al 2010). However, in an interesting comparison of transformed rat cell lines from brain capillary endothelial cells and retinal capillary endothelial cells, Ohtsuki et al found dominant expression of AR in the brain capillary cells, but not the retinal capillary cells.…”