Growth factor midkine is involved in the pathogenesis of diabetic nephropathy
Growth factor midkine is involved in the pathogenesis of diabetic nephropathy
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DOI：
10.2353/ajpath.2006.050488
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发表时间：
2006-01-01
影响因子：
6
通讯作者：
Kadomatsu, K
中科院分区：
文献类型：
--
作者：
Kosugi, T;Yuzawa, Y;Kadomatsu, K
糖尿病肾病是一种与糖尿病相关的危及生命的疾病。长期高血糖可引起肾小球系膜细胞的病理反应，如细胞外基质的过度生成，最终导致肾病。然而，其发病机制尚未完全阐明。使用链脲佐菌素诱导的糖尿病模型，我们报告了生长因子中期因子（Mdk-/-）缺陷的小鼠比Mdk+/+小鼠表现出明显较轻的肾病，即使这两种小鼠在注射链脲佐菌素后表现出相似的高血糖程度。在糖尿病肾病Mdk+/+小鼠的肾小球系膜和暴露于高糖的原代培养的系膜细胞中诱导中期因子表达。在高糖负荷下，Mdk-/-系膜细胞表现出蛋白激酶C和细胞外信号调节激酶的磷酸化减少以及转化生长因子-P的产生减少。添加外源性中期因子恢复细胞外信号调节激酶磷酸化。在高糖条件下，在Mdk-/-细胞中，而中期因子反义寡核苷酸抑制Mdk+/+细胞中的中期因子。因此，本研究确定中期因子是糖尿病肾病的关键分子，并表明中期因子加速肾病高血糖引起的细胞内信号网络。
Diabetic nephropathy is a life-threatening disease associated with diabetes mellitus. Longstanding hyperglycemia induces pathological reactions of glomerular mesangial cells, such as overproduction of extraceflular matrix, which finally lead to nephropathy. However, the mechanisms underlying its pathogenesis have not been completely elucidated. Using the Streptozotocin-induced model of diabetes, we report that mice deficient in the growth factor midkine (Mdk-/-) exhibited strikingly milder nephropathy than Mdk+/+ mice, even though both mice showed similar extents of hyperglycemia after Streptozotocin injection. Midkine expression was induced in the glomerular mesangium of Mdk+/+ mice with diabetic nephropathy and in primary cultured mesangial cells exposed to high glucose. Mdk-/- mesangial cells exhibited reduced phosphorylation of protein kinase C and extracelhilar signal-regulated kinase as well as reduced production of transforming growth factor-P, on high glucose loading. Addition of exogenous midkine restored extracellular signal-regulated kinase phosphorylation. in Mdk-/- cells under high glucose conditions, whereas a midkine antisense oligodeoxynucleotide suppressed midkine in Mdk+/+ cells. Therefore, this study identifies midkine as a key molecule in diabetic nephropathy and suggests that midkine accelerates the intracellular signaling network evoked by hyperglycemia in nephropathy.