PURPOSE.To quantify and evaluate the distribution of angiotensin II (Ang II) and its receptors in the human retina. METHODS. Donor eyes were obtained within 12 hours postmortem and classified as hypertensive or normotensive and diabetic or nondiabetic, based on the donors' medical histories. Ang II in retina and vitreous was quantified by RIA. Ang II receptors were characterized and quantified by competitive membrane-binding assays. Ang II, its heptapeptide metabolite Ang-(1-7), and AT1 and AT2 receptors were localized by immunohistochemistry and confocal imaging. RESULTS. Levels of Ang II in the retina were significantly higher than in vitreous (P Ͻ 0.05). Ang II in the diabetic retina had a higher median compared with that in the nondiabetic retina. Ang II and Ang-(1-7) colocalized in retinal Müller cells. The retina had the highest levels of Ang II receptors that were significantly higher than the optic nerve, retinal pigment epithelium-choroid complex, and ciliary body-iris complex (P Ͻ 0.05). AT1 receptors were more abundant than AT2 receptors in the retina. Immunoreactivity for AT1 was detected in Müller cells and on blood vessels. AT2 receptors were localized throughout the Müller cells and nuclei of ganglion cells and neurons in the inner nuclear layer. CONCLUSIONS. In the human retina, identification of Ang II and its bioactive metabolite Ang-(1-7) in Müller cells suggests that these glial cells are able to produce and process Ang II. Ang receptors were localized in the blood vessels and neural cells. Local Ang II signaling may thus allow for autoregulation of neurovascular activity. Such an autonomous system could modulate the onset and severity of retinovascular disease. (Invest Ophthalmol Vis Sci. 2007;48:3301-3311) DOI:10.1167/iovs.06-1024 D iabetic retinopathy is one of the major complications of diabetes mellitus and the leading cause of visual loss and blindness in the adult population of the United States. It has been viewed as a disorder of the retinal vasculature 1,2 ; however, evidence from numerous reports indicate that neural function of the retina is compromised before the vascular lesions are clinically diagnosed. At the cellular level, diabetes alters the structure and function of most cell types.3-9 Many factors have been implicated in the pathogenesis of diabetic retinopathy. Clinical and experimental studies have shown that the renin-angiotensin system (RAS) plays a pivotal role in the progression of the disease, presumably through local changes in blood flow and production of vascular endothelial growth factor (VEGF 10 -22 ). Furthermore, Ang II may act as an inflammatory agent by enhancing vascular permeability through prostaglandins and VEGF 23 and contribute to the recruitment of inflammatory cells by inducing chemokines and adhesion molecules. 23,24 Although an independent RAS has not been established in the retina, many reports support the concept of a paracrine RAS in this organ. [25][26][27][28] In the classic pathway, Ang II is produced by the sequential processing of plasma...
The sex discordance in COVID-19 outcomes has been widely recognized, with males generally faring worse than females and a potential link to sex steroids. A plausible mechanism is androgen-induced expression of TMPRSS2 and/or ACE2 in pulmonary tissues that may increase susceptibility or severity in males. This hypothesis is the subject of several clinical trials of anti-androgen therapies around the world. Here, we investigated the sex-associated TMPRSS2 and ACE2 expression in human and mouse lungs and interrogated the possibility of pharmacologic modification of their expression with anti-androgens. We found no evidence for increased TMPRSS2 expression in the lungs of males compared to females in humans or mice. Furthermore, in male mice, treatment with the androgen receptor antagonist enzalutamide did not decrease pulmonary TMPRSS2. On the other hand, ACE2 and AR expression was sexually dimorphic and higher in males than females. ACE2 was moderately suppressible with enzalutamide administration. Our work suggests that sex differences in COVID-19 outcomes attributable to viral entry are independent of TMPRSS2. Modest changes in ACE2 could account for some of the sex discordance.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.