Twisted gastrulation, a BMP antagonist, exacerbates podocyte injury.
Twisted gastrulation, a BMP antagonist, exacerbates podocyte injury.
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DOI：
10.1371/journal.pone.0089135
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Yanagita M
中科院分区：
文献类型：
--
作者：
Yamada S;Nakamura J;Asada M;Takase M;Matsusaka T;Iguchi T;Yamada R;Tanaka M;Higashi AY;Okuda T;Asada N;Fukatsu A;Kawachi H;Graf D;Muso E;Kita T;Kimura T;Pastan I;Economides AN;Yanagita M
足细胞损伤是肾小球硬化进展的第一步。以往的研究已经证明骨形态发生蛋白7(Bmp7)在足细胞损伤中的有益作用以及足细胞中存在天然的BMP信号。Bmp7的局部活性由细胞型特异性BMP拮抗剂控制，这些拮抗剂抑制Bmp7与其受体的结合。在这里，我们证明了BMP拮抗剂Twisted原肠形成的产物(Twsg1)是足细胞BMP功能的中心负调节因子，Twsg1基因缺失的小鼠对足细胞损伤具有抵抗力。Twsg1是培养的小鼠足细胞中含量最丰富的BMP拮抗剂。BMP通过Smad信号诱导足细胞分化，而同时给予Twsg1则拮抗这一作用。给予BMP也可抑制足细胞的增殖，而同时给予Twsg1则可拮抗该作用。Twsg1在健康肾脏的肾小球壁细胞(PECs)和远端肾单位中表达，在足细胞损伤的小鼠模型中也表达于受损的肾小球细胞。Twsg1基因缺失的小鼠在足细胞损伤模型中表现出较轻的低蛋白血症和高脂血症，组织学改变较轻，同时保持足细胞标志物的表达。综上所述，我们的结果表明Twsg1在Bmp7对足细胞保护作用的调节中起着关键作用，抑制Twsg1是开发新的足细胞损伤治疗方法的一种有前途的手段。
Podocyte injury is the first step in the progression of glomerulosclerosis. Previous studies have demonstrated the beneficial effect of bone morphogenetic protein 7 (Bmp7) in podocyte injury and the existence of native Bmp signaling in podocytes. Local activity of Bmp7 is controlled by cell-type specific Bmp antagonists, which inhibit the binding of Bmp7 to its receptors. Here we show that the product of Twisted gastrulation (Twsg1), a Bmp antagonist, is the central negative regulator of Bmp function in podocytes and that Twsg1 null mice are resistant to podocyte injury. Twsg1 was the most abundant Bmp antagonist in murine cultured podocytes. The administration of Bmp induced podocyte differentiation through Smad signaling, whereas the simultaneous administration of Twsg1 antagonized the effect. The administration of Bmp also inhibited podocyte proliferation, whereas simultaneous administration of Twsg1 antagonized the effect. Twsg1 was expressed in the glomerular parietal cells (PECs) and distal nephron of the healthy kidney, and additionally in damaged glomerular cells in a murine model of podocyte injury. Twsg1 null mice exhibited milder hypoalbuminemia and hyperlipidemia, and milder histological changes while maintaining the expression of podocyte markers during podocyte injury model. Taken together, our results show that Twsg1 plays a critical role in the modulation of protective action of Bmp7 on podocytes, and that inhibition of Twsg1 is a promising means of development of novel treatment for podocyte injury.
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