Department of Medicine/Nephrology, Hannover Medical School, Hannover, Germany; Mount Desert Island Biological Laboratory, Salisbury Cove, Maine, USA.
Department of Medicine/Nephrology, Hannover Medical School, Hannover, Germany; Mount Desert Island Biological Laboratory, Salisbury Cove, Maine, USA.
Kidney Int. 2017 Oct;92(4):836-849. doi: 10.1016/j.kint.2017.03.005. Epub 2017 May 3.
The pathophysiology of many proteinuric kidney diseases is poorly understood, and microRNAs (miRs) regulation of these diseases has been largely unexplored. Here, we tested whether miR-378a-3p is a novel regulator of glomerular diseases. MiR-378a-3p has two predicted targets relevant to glomerular function, the glomerular basement membrane matrix component, nephronectin (NPNT), and vascular endothelial growth factor VEGF-A. In zebrafish (Danio rerio), miR-378a-3p mimic injection or npnt knockdown by a morpholino oligomer caused an identical phenotype consisting of edema, proteinuria, podocyte effacement, and widening of the glomerular basement membrane in the lamina rara interna. Zebrafish vegf-A protein could not rescue this phenotype. However, mouse Npnt constructs containing a mutated 3'UTR region prevented the phenotype caused by miR-378a-3p mimic injection. Overexpression of miR-378a-3p in mice confirmed glomerular dysfunction in a mammalian model. Biopsies from patients with focal segmental glomerulosclerosis and membranous nephropathy had increased miR-378a-3p expression and reduced glomerular levels of NPNT. Thus, miR-378a-3p-mediated suppression of the glomerular matrix protein NPNT is a novel mechanism for proteinuria development in active glomerular diseases.
许多蛋白尿性肾脏疾病的病理生理学机制尚未得到充分理解，miRNAs（microRNAs）对这些疾病的调节作用也在很大程度上尚未得到探索。在这里，我们测试了 miR-378a-3p 是否是一种新型的肾小球疾病调控因子。miR-378a-3p 有两个与肾小球功能相关的预测靶点，肾小球基底膜基质成分 Nephrin（NPNT）和血管内皮生长因子 VEGF-A。在斑马鱼（Danio rerio）中，miR-378a-3p 模拟物注射或通过 morpholino 寡核苷酸对 NPNT 的敲低导致了一种相同的表型，包括水肿、蛋白尿、足细胞消失和肾小球基底膜内疏松层的增宽。斑马鱼 Vegf-A 蛋白不能挽救这种表型。然而，包含突变 3'UTR 区域的小鼠 Npnt 构建体可阻止 miR-378a-3p 模拟物注射引起的表型。miR-378a-3p 在小鼠中的过表达证实了哺乳动物模型中的肾小球功能障碍。局灶节段性肾小球硬化症和膜性肾病患者的活检显示 miR-378a-3p 表达增加，肾小球 NPNT 水平降低。因此，miR-378a-3p 介导的肾小球基质蛋白 NPNT 的抑制是活动性肾小球疾病中蛋白尿发展的一种新机制。
