MicroRNA-21 in Glomerular Injury
MicroRNA-21 in Glomerular Injury
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DOI：
10.1681/asn.2013121274
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发表时间：
2015-04-01
影响因子：
13.6
通讯作者：
Bitzer, Markus
中科院分区：
文献类型：
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作者：
Lai, Jennifer Y.;Luo, Jihghui;Bitzer, Markus
TGF-β(1) 是一种多效性生长因子，可介导肾小球硬化和足细胞凋亡（肾小球疾病的标志）。 microRNA-21 (miR-21) 的表达受 TGF-beta(1) 调节，miR-21 抑制癌细胞凋亡。 TGF-β(1) 转基因小鼠表现出足细胞加速丢失和肾小球硬化。我们确定，在暴露于 TGF-β(1) 后，培养的鼠足细胞中 miR-21 表达迅速增加，并且 TGF-β(1) 转基因小鼠肾脏中的 miR-21 表达高于野生型小鼠。与 miR-21 野生型 TGF-β(1) 转基因同窝小鼠相比，miR-21 缺陷的 TGF-β(1) 转基因小鼠表现出蛋白尿和肾小球细胞外基质沉积增加，并且每个肾小球簇的足细胞更少。同样，链脲佐菌素诱导的糖尿病小鼠中 miR-21 表达增加，这些小鼠中 miR-21 的缺失与白蛋白尿增加、足细胞耗竭和系膜扩张相关。在培养的足细胞中，抑制 miR-21 伴随着细胞死亡率、TGF-β/Smad3 信号活性以及已知促凋亡 miR-21 靶基因 p53、Pdcd4、Smad7、Tgfbr2 和 Timp3 表达的增加。在美国-印度糖尿病肾病患者 (n=48) 中，白蛋白与肌酐比值与肾小球分数中的 nniR-21 表达呈正相关 (r=0.6；P
TGF-beta(1) is a pleotropic growth factor that mediates glomerulosclerosis and podocyte apoptosis, hallmarks of glomerular diseases. The expression of microRNA-21 (miR-21) is regulated by TGF-beta(1), and miR-21 inhibits apoptosis in cancer cells. TGF-beta(1)-transgenic mice exhibit accelerated podocyte loss and glomerulosclerosis. We determined that miR-21 expression increases rapidly in cultured murine podocytes after exposure to TGF-beta(1) and is higher in kidneys of TGF-beta(1)-transgenic mice than wild-type mice. miR-21-deficient TGF-beta(1)-transgenic mice showed increased proteinuria and glomerular extracellular matrix deposition and fewer podocytes per glomerular tuft compared with miR-21 wild-type TGF-beta(1)-transgenic littermates. Similarly, miR-21 expression was increased in streptozotocin-induced diabetic mice, and loss of miR-21 in these mice was associated with increased albuminuria, podocyte depletion, and mesangial expansion. In cultured podocytes, inhibition of miR-21 was accompanied by increases in the rate of cell death, TGF-beta/Smad3-signaling activity, and expression of known proapoptotic miR-21 target genes p53, Pdcd4, Smad7, Tgfbr2, and Timp3. In American-Indian patients with diabetic nephropathy (n=48), albumin-to-creatinine ratio was positively associated with nniR-21 expression in glomerular fractions (r=0.6; P