Glut9 is a major regulator of urate homeostasis and its genetic inactivation induces hyperuricosuria and urate nephropathy
Glut9 is a major regulator of urate homeostasis and its genetic inactivation induces hyperuricosuria and urate nephropathy
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DOI：
10.1073/pnas.0904411106
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发表时间：
2009-09-08
影响因子：
11.1
通讯作者：
Thorens, Bernard
中科院分区：
文献类型：
--
作者：
Preitner, Frederic;Bonny, Olivier;Thorens, Bernard
血浆尿酸水平升高与代谢、心血管和肾脏疾病有关。尿酸也可形成晶体，可沉积在关节引起痛风和肾小管引起肾结石。在小鼠中，血浆尿酸水平受肝脏分解以及不完全了解的肾脏重吸收和分泌过程的控制。在这里，我们研究了最近发现的谷氨酸转运蛋白Glut9在小鼠体内或肝脏特异性谷氨酸9基因失活的生理控制中的作用。我们发现Glut9在肝细胞的基底外膜和远端肾元的根尖膜和基底外膜中表达。全身性敲除Glut9的小鼠表现为中度高尿酸血症、大量高尿酸血症和早发性肾病，其特征为梗阻性结石、小管间质炎症和皮质进行性炎性纤维化，以及轻度肾功能不全。相反，在没有尿酸肾病或任何肾脏结构异常的情况下，成年小鼠的肝脏特异性Glut9基因失活会导致严重的高尿酸血症和高尿酸尿。综上所述，我们的数据表明，Glut9通过其在肾脏处理和肝脏摄取尿酸的双重作用，在尿酸稳态中发挥重要作用。
Elevated plasma urate levels are associated with metabolic, cardiovascular, and renal diseases. Urate may also form crystals, which can be deposited in joints causing gout and in kidney tubules inducing nephrolithiasis. In mice, plasma urate levels are controlled by hepatic breakdown, as well as, by incompletely understood renal processes of reabsorption and secretion. Here, we investigated the role of the recently identified urate transporter, Glut9, in the physiological control of urate homeostasis using mice with systemic or liver-specific inactivation of the Glut9 gene. We show that Glut9 is expressed in the basolateral membrane of hepatocytes and in both apical and basolateral membranes of the distal nephron. Mice with systemic knockout of Glut9 display moderate hyperuricemia, massive hyperuricosuria, and an early-onset nephropathy, characterized by obstructive lithiasis, tubulointerstitial inflammation, and progressive inflammatory fibrosis of the cortex, as well as, mild renal insufficiency. In contrast, liver-specific inactivation of the Glut9 gene in adult mice leads to severe hyperuricemia and hyperuricosuria, in the absence of urate nephropathy or any structural abnormality of the kidney. Together, our data show that Glut9 plays a major role in urate homeostasis by its dual role in urate handling in the kidney and uptake in the liver.