Abstract
Prostaglandins are important regulators of female reproductive functions to which aldose reductases exhibiting hydroxysteroid dehydrogenase activity also contribute. Our work on the regulation of reproductive function by prostaglandins (PGs), lead us to the discovery that AKR1B5 and later AKR1B1were highly efficient and physiologically relevant PGF synthases. PGE2 and PGF2α are the main prostanoids produced in the human endometrium and proper balance in their relative production is important for normal menstruation and optimal fertility. Recent evidence suggests that PGE2/EP2 and PGF2α/FP may constitute a functional dyad with physiological relevance comparable to the prostacyclin-thromboxane dyad in the vascular system. We have recently reported that AKR1B1 was expressed and modulated in association with PGF2α production in response to IL-1β in the human endometrium. In the present study, we show that the human AKR1B1 (gene ID: 231) also known as ALDR1 or ALR2 is a functional PGF2α synthase in different models of living cells and tissues. Using human endometrial cells, prostate, and vascular smooth muscle cells, cardiomyocytes and endothelial cells we demonstrate that IL-1β is able to up regulate COX-2 and AKR1B1 proteins as well as PGF2α production under normal glucose concentrations. We show that the promoter activity of AKR1B1 gene is increased by IL-1β particularly around the multiple stress response region containing two putative antioxidant response elements adjacent to TonE and AP1. We also show that AKR1B1 is able to regulate PGE2 production through PGF2α acting on its FP receptor and that aldose reductase inhibitors like alrestatin, Statil (ponalrestat), and EBPC exhibit distinct and characteristic inhibition of PGF2α production in different cell models. The PGF synthase activity of AKR1B1 represents a new and important target to regulate ischemic and inflammatory responses associated with several human pathologies.
Highlights
The human aldose reductase ALR2 gene AKR1B1 is a notorious enzyme which has been associated with complications of diabetes for more than four decades (Srivastava et al, 2005)
Normal menstruation depend on an equilibrium between vasoconstrictors such as PGF2α (Lockwood and Schatz, 1996; Sales and Jabbour, 2003a) and vasodilators such as PGE2 or nitric oxide (NO) (Tschugguel et al, 1999)
Both AKR1B1 and AKR1C3 enzymes are present in the endometrium throughout the menstrual cycle
Summary
The human aldose reductase ALR2 gene AKR1B1 is a notorious enzyme which has been associated with complications of diabetes for more than four decades (Srivastava et al, 2005). AKR1B1 is considered as the rate limiting enzyme of the polyol pathway responsible for the conversion of glucose into sorbitol. While searching for the enzyme responsible for the production of PGF2α in the endometrium, we made the serendipitous and unexpected discovery that AKR1B5 (Madore et al, 2003) and later the human aldose reductase AKR1B1 (Bresson et al, 2011) were highly functional PGFS. PGH2 produced by COXs is the common precursor of all PGs generated by specific terminal synthases such as PGF synthase for PGF2α and PGE synthase for PGE2.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
