The excretion and reabsorption of uric acid both to and from urine are tightly regulated by uric acid transporters. Metabolic syndrome conditions, such as obesity, hypercholesterolemia, and insulin resistance, are believed to regulate the expression of uric acid transporters and decrease the excretion of uric acid. However, the mechanisms driving cholesterol impacts on uric acid transporters have been unknown. Here, we show that cholesterol metabolite 27‐hydroxycholesterol (27HC) upregulates the uric acid reabsorption transporter URAT1 encoded by SLC22A12 via estrogen receptors (ER). Transcriptional motif analysis showed that the SLC22A12 gene promoter has more estrogen response elements (EREs) than other uric acid reabsorption transporters such as SLC22A11 and SLC22A13, and 27HC‐activated SLC22A12 gene promoter via ER through EREs. Furthermore, 27HC increased SLC22A12 gene expression in human kidney organoids. Our results suggest that in hypercholesterolemic conditions, elevated levels of 27HC derived from cholesterol induce URAT1/SLC22A12 expression to increase uric acid reabsorption, and thereby, could increase serum uric acid levels.

Cooling-induced reduction of skin blood flow results from a reflex increase in sympathetic output and an enhanced vasoconstrictor activity of skin vessels. The latter has been proposed to be mediated by increased reactivity of α2C-adrenoceptors during cooling in studies with isolated cutaneous vessels in vitro. We have previously shown in studies with tetrodotoxin-treated mice in vivo that reduction of plantar skin blood flow (PSBF) induced by local cooling results primarily from increased reactivity of α2C-adrenoceptors. In addition, we showed that part of the cooling-induced response was also mediated by α1-adrenoceptors. However, the mechanisms involved in the cooling-induced responses mediated by α1-adrenoceptors have not been elucidated. The present study is an investigation seeking to clarify the mechanisms involving α1-adrenoceptors. Medial plantar arteries were isolated from male ddY mice and changes in vessel diameter were measured in vitro using pressurized arteriography. In vivo measurements of PSBF were performed on artificially ventilated tetrodotoxin treated mice, anaesthetized with pentobarbital sodium, using laser Doppler flowmetry, with the probe positioned above the medial plantar artery. In the in vitro studies with isolated plantar arteries, cooling from 37 to 28°C did not affect the constrictor potency of phenylephrine, an α1-adrenoceptor agonist, and the threshold concentration to evoke constriction was rather higher at 28°C than it was at 37°C. The cooling also suppressed the constrictor efficacy of UK14,304, an α2-adrenoceptor agonist. In contrast, cooling the air temperature around the foot from 25 to 10°C in vivo decreased PSBF, which was significantly inhibited by phentolamine, an α-adrenoceptor antagonist, although MK-912, an α2C-adrenoceptor antagonist, had no effect on it. These results suggest that although α1-adrenoceptors are involved in cooling-induced reduction of PSBF in mice, the response is unlikely to result from an enhancement of α1-adrenoceptormediated vasoconstriction of plantar arteries during cooling.

Summary Regenerative medicine relies on basic research outcomes that are only practical when cost effective. The human eyeball requires the retinal pigment epithelium (RPE) to interface the neural retina and the choroid at large. Millions of people suffer from age-related macular degeneration (AMD), a blinding multifactor genetic disease among RPE degradation pathologies. Recently, autologous pluripotent stem-cell-derived RPE cells were prohibitively expensive due to time; therefore, we developed a faster reprogramming system. We stably induced RPE-like cells (iRPE) from human fibroblasts (Fibs) by conditional overexpression of both broad plasticity and lineage-specific transcription factors (TFs). iRPE cells displayed critical RPE benchmarks and significant in vivo integration in transplanted retinas. Herein, we detail the iRPE system with comprehensive single-cell RNA sequencing (scRNA-seq) profiling to interpret and characterize its best cells. We anticipate that our system may enable robust retinal cell induction for basic research and affordable autologous human RPE tissue for regenerative cell therapy.