In conclusion we have shown that AKR

In conclusion, we have shown that AKR1D1 regulates glucocorticoid availability and GR activation and therefore represents a key pre-receptor regulator of hormonal action in human liver. However, there are additional questions that need to be addressed including dissecting the broader role of AKR1D1 in an in vivo context in both rodents and humans.
Financial support
Disclosure summary
Acknowledgments This work was supported by the Medical Research Council, UK (programme grant awarded to JWT, ref. MR/P011462/1); NIHR Oxford Biomedical Research Centre (Principal investigator award to JWT) based at Oxford University Hospitals NHS Trust and University of Oxford; British Heart Foundation (senior fellowship awarded to LH ref. FS/15/56/31645); NIHR Birmingham Biomedical Research Centre (Principal investigator award to WA); JED is supported by NIHR Oxford Biomedical Research Centre, Oxford UK. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health or the National Institute of Environmental Health.
Introduction
Actions of glucocorticoids in the eye
Concluding remarks Glucocorticoids are among the most widely prescribed drugs in the ophthalmology practice (Fig. 2). Given the complexity of glucocorticoid signaling and transcriptional activity, it is becoming clear that most of GCs' clinical application in ophthalmology lacks knowledge of GC actions at the molecular and physiological levels. Advances in understanding the physiological role of GCs, specifically in the eye, are vital for the development of optimized targeted GC therapies of specific, and potent anti-inflammatory potential with minimal adverse effects. The current findings reinforce the need for appropriate animal models with conditional 1400w of GR in specific tissues of the eye- cornea, lens, TM, retina, and RPE/choroid to dissect the mechanism of GR signaling in individual ocular layers, and then advance to understand the cross talk between them. Needless to mention that in vivo experiment in the eyes should be performed in male and female animals to account for the sexual dimorphic effects of GCs, that continued to be observed in different organs. Furthermore, using high doses of GCs in the ophthalmology clinics is a major drawback that could be contributing to the development of GC-induced complications. Therefore, it is important to study ocular glucocorticoid signaling mechanisms using dose and time-gradient of GCs to eventually characterize the lowest functional dose and optimal time point with maximum benefit and least side effects.
Acknowledgments
Introduction Canonical glucocorticoid transcriptional regulation is mediated by glucocorticoid binding to the intracellular glucocorticoid receptor (GR), translocation of the liganded GR complex to the nucleus, and binding of the GR to the glucocorticoid response element (GRE) or to other transcription factors [1]. Trafficking of the GR from the cytosol to the nucleus is the first step, following glucocorticoid binding, in the transcriptional regulatory cascade of the activated GR, and occurs within minutes of ligand binding [2]. In the absence of steroid, the unliganded GR is bound to chaperone proteins as part of a complex that is transcriptionally inactive. However, an equilibrium exists between the cytosolic and nuclear GR in the absence of ligand [3], indicating that shuttling of the GR between the cytosol and nucleus occurs in the absence of steroid, although the signal(s) that stimulate(s) the trafficking of unliganded GR and the transcriptional functionality of the unliganded GR are not well understood. A GRα isoform, GRα-D, is expressed in neurons at varying levels during different developmental stages [4], and can be found in the nucleus of glucocorticoid-free cells and associated with GRE-containing promoters in the absence of glucocorticoid [5]. Although the cellular actions of unliganded GR in the nucleus are not fully understood, there is evidence from a mouse mammary cell line that unliganded GR is capable of both negatively and positively regulating gene transcription [6]. Some cellular conditions can induce nuclear localization of the unliganded GR, including heat shock [7] and shear stress [8]. Under shear stress conditions, such as those experienced by aortic endothelial cells, the unliganded GR has been reported to regulate gene transcription [8].