1.Hyperuricemia induces hypertension through activation of renal epithelial sodium channel (ENaC).
Xu W1, Huang Y2, Li L2, Sun Z2, Shen Y2, Xing J2, Li M2, Su D3, Liang X4. Metabolism. 2016 Mar;65(3):73-83. doi: 10.1016/j.metabol.2015.10.026. Epub 2015 Oct 26.
OBJECTIVES: The mechanisms leading to hypertension associated with hyperuricemia are still unclear. The activity of the distal nephron epithelial sodium channel (ENaC) is an important determinant of sodium balance and blood pressure. Our aim was to investigate whether the effect of hyperuricemia on blood pressure is related to ENaC activation.
2.Stronger Uricosuric Effects of the Novel Selective URAT1 Inhibitor UR-1102 Lowered Plasma Urate in Tufted Capuchin Monkeys to a Greater Extent than Benzbromarone.
Ahn SO1, Ohtomo S1, Kiyokawa J1, Nakagawa T1, Yamane M1, Lee KJ1, Kim KH1, Kim BH1, Tanaka J1, Kawabe Y1, Horiba N2. J Pharmacol Exp Ther. 2016 Apr;357(1):157-66. doi: 10.1124/jpet.115.231647. Epub 2016 Feb 23.
Urate-lowering therapy is indispensable for the treatment of gout, but available drugs do not control serum urate levels tightly enough. Although the uricosurics benzbromarone and probenecid inhibit a urate reabsorption transporter known as renal urate transporter 1 (URAT1) and thus lower serum urate levels, they also inhibit other transporters responsible for secretion of urate into urine, which suggests that inhibiting URAT1 selectively would lower serum urate more effectively. We identified a novel potent and selective URAT1 inhibitor, UR-1102, and compared its efficacy with benzbromarone in vitro and in vivo. In human embryonic kidney (HEK)293 cells overexpressing URAT1, organic anion transporter 1 (OAT1), and OAT3, benzbromarone inhibited all transporters similarly, whereas UR-1102 inhibited URAT1 comparably to benzbromarone but inhibited OAT1 and OAT3 quite modestly. UR-1102 at 3-30 mg/kg or benzbromarone at 3-100 mg/kg was administered orally once a day for 3 consecutive days to tufted capuchin monkeys, whose low uricase activity causes a high plasma urate level.
3.Intrahepatic bile ducts are developed through formation of homogeneous continuous luminal network and its dynamic rearrangement.
Tanimizu N1, Kaneko K2, Itoh T2, Ichinohe N1, Ishii M1,3, Mizuguchi T3, Hirata K3, Miyajima A2, Mitaka T1. Hepatology. 2016 Feb 29. doi: 10.1002/hep.28521. [Epub ahead of print]
The intrahepatic bile duct (IHBD) is a highly organized tubular structure consisting of cholangiocytes, biliary epithelial cells, which drains bile produced by hepatocytes into the duodenum. Although several models have been proposed, it remains unclear how the three-dimensional (3D) IHBD network develops during liver organogenesis. Using 3D imaging techniques, we demonstrate that the continuous luminal network of IHBDs is established by one week after birth. Beyond this stage, the IHBD network consists of large ducts running along portal veins (PVs) and small ductules forming a mesh-like network around PVs. By analyzing embryonic and neonatal livers, we found that newly differentiated cholangiocytes progressively form a continuous and homogeneous luminal network. Elongation of this continuous network toward the liver periphery was attenuated by a potent Notch signaling inhibitor DAPT. Following this first step, the fine homogenous network is reorganized into the mature hierarchical network consisting of large ducts and small ductules.