Hemicentin 1 influences podocyte dynamic changes in glomerular diseases
Hemicentin 1 influences podocyte dynamic changes in glomerular diseases
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DOI：
10.1152/ajprenal.00198.2017
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发表时间：
2018-06-01
影响因子：
4.2
通讯作者：
Desvergne, Beatrice
中科院分区：
文献类型：
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作者：
Toffoli, Barbara;Zennaro, Cristina;Desvergne, Beatrice
不同的复杂机制控制足细胞足突的形态及其与基底膜的相互作用。这个系统的损伤通常会导致肾小球功能障碍和蛋白尿。本研究旨在确定糖尿病肾病肾小球损害的早期标志物。为此，我们对3周大的过氧化体增殖物激活受体-γ(PPAR-Gamma)缺失和Azip/F1小鼠的肾脏进行了微阵列分析，这是脂肪营养不良引起的糖尿病肾病的两个模型。随后对丰富的基因簇进行了功能注释。肾小球损伤早期的显著变化之一是半胱氨酸蛋白1(HMCN1)的增加。然后用实时定量聚合酶链式反应和免疫荧光技术研究其在不同肾小球损伤模型和足细胞培养中的表达和分布。根据疾病的严重程度，糖尿病小鼠的肾小球中HMCN1逐渐增加，在氨基核苷(PA)治疗的大鼠中也是如此。对小鼠和人足细胞的研究表明，在不同的病理刺激下，如高血糖、转化生长因子-β(TGF-β)和PA，HMCN1的沉积增加。体外沉默研究表明，HMCN1介导了转化生长因子-β诱导的足细胞骨架重排。最后，我们证明了HMCN1在蛋白尿性肾病患者的肾脏中的表达增加。综上所述，我们的研究确定HMCN1是一个参与足细胞足突动态变化的新分子。与足细胞功能障碍相关的HMCN1的表达增加表明，HMCN1可能是不同蛋白尿性肾病早期肾小球损伤的标志。
Different complex mechanisms control the morphology of podocyte foot processes and their interactions with the underlying basement membrane. Injuries to this system often cause glomerular dysfunction and albuminuria. The present study aimed at identifying early markers of glomerular damage in diabetic nephropathy. For this purpose, we performed a microarray analysis on kidneys of 3-wk-old peroxisome proliferator-activated receptor-gamma (PPAR gamma)-null and AZIP/F1 mice, which are two models of diabetic nephropathy due to lipodystrophy. This was followed by functional annotation of the enriched clusters of genes. One of the significant changes in the early stages of glomerular damage was the increase of hemicentin 1 (HMCN1). Its expression and distribution were then studied by real-time PCR and immunofluorescence in various models of glomerular damage and on podocyte cell cultures. HMCN1 progressively increased in the glomeruli of diabetic mice, according to disease severity, as well as in puromycin aminonucleoside (PA)-treated rats. Studies on murine and human podocytes showed an increased HMCN1 deposition upon different pathological stimuli, such as hyperglycemia, transforming growth factor-beta (TGF-beta), and PA. In vitro silencing studies showed that HMCN1 mediated the rearrangements of podocyte cytoskeleton induced by TGF-beta. Finally, we demonstrated an increased expression of HMCN1 in the kidneys of patients with proteinuric nephropathies. In summary, our studies identified HMCN1 as a new molecule involved in the dynamic changes of podocyte foot processes. Its increased expression associated with podocyte dysfunction points to HMCN1 as a possible marker for the early glomerular damage occurring in different proteinuric nephropathies.