Uterine sensitization-associated gene-1 (USAG-1), a novel BMP antagonist expressed in the kidney, accelerates tubular injury
Uterine sensitization-associated gene-1 (USAG-1), a novel BMP antagonist expressed in the kidney, accelerates tubular injury
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DOI：
10.1172/jci25445
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发表时间：
2006-01-01
影响因子：
15.9
通讯作者：
Sakurai, T
中科院分区：
文献类型：
--
作者：
Yanagita, M;Okuda, T;Sakurai, T
透析依赖性是世界上发病率和死亡率的主要原因之一，并且一旦发展为终末期肾病，其无法通过目前可用的治疗逆转。虽然大剂量的骨形态发生蛋白-7（BMP-7）的施用已被证明可以修复已建立的肾损伤并改善肾功能，但是内源性BMP-7的病理生理作用及其活性的调节机制仍然是难以捉摸的。在这里，我们表明，子宫致敏相关基因-1（USAG 1），一种新的BMP拮抗剂，在肾脏中大量表达的产品，是肾脏中BMP功能的中心负调节因子，并且缺乏USAG 1的小鼠（USAG 1（-/-）小鼠）对肾损伤具有抗性。USAG 1（-/-）小鼠在急性和慢性肾损伤模型中表现出延长的存活时间和保留的肾功能。通过Smad蛋白磷酸化评估的肾BMP信号传导在具有肾损伤的USAG 1（-/-）小鼠中显著增强，表明肾功能的保持归因于内源性BMP信号传导的增强。此外，施用针对BMP-7的中和抗体消除了USAG 1（-/-）小鼠中的肾保护，表明USAG-I在BMP的肾保护作用的调节中起关键作用，并且USAG-I的抑制是开发肾脏疾病的新治疗的有希望的手段。
Dialysis dependency is one of the leading causes of morbidity and mortality in the world, and once end-stage renal disease develops, it cannot be reversed by currently available therapy. Although administration of large doses of bone morphogenetic protein-7 (BMP-7) has been shown to repair established renal injury and improve renal function, the pathophysiological role of endogenous BMP-7 and regulatory mechanism of its activities remain elusive. Here we show that the product of uterine sensitization-associated gene-1 (USAG1), a novel BMP antagonist abundantly expressed in the kidney, is the central negative regulator of BMP function in the kidney and that mice lacking USAG-1 (USAG1(-/-) mice) are resistant to renal injury. USAG1(-/-) mice exhibited prolonged survival and preserved renal function in acute and chronic renal injury models. Renal BMP signaling, assessed by phosphorylation of Smad proteins, was significantly enhanced in USAG1(-/-) mice with renal injury, indicating that the preservation of renal function is attributable to enhancement of endogenous BMP signaling. Furthermore, the administration of neutralizing antibody against BMP-7 abolished renoprotection in USAG1(-/-) mice, indicating that USAG-1 plays a critical role in the modulation of renoprotective action of BMP and that inhibition of USAG-1 is a promising means of development of novel treatment for renal diseases.