Division of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada.
Division of Nephrology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
Int J Mol Sci. 2018 Feb 6;19(2):479. doi: 10.3390/ijms19020479.
Nephrotic syndrome is a kidney disease featured by heavy proteinuria. It is caused by injury to the specialized epithelial cells called "podocytes" within the filtration unit of the kidney, glomerulus. Previous studies showed that hyperactivation of the RhoGTPase, Rac1, in podocytes causes podocyte injury and glomerulosclerosis (accumulation of extracellular matrix in the glomerulus). However, the mechanism by which Rac1 is activated during podocyte injury is unknown. Trio is a guanine nucleotide exchange factor (GEF) known to activate Rac1. By RNA-sequencing, we found that Trio mRNA is abundantly expressed in cultured human podocytes. Trio mRNA was also significantly upregulated in humans with minimal change disease and focal segmental glomerulosclerosis, two representative causes of nephrotic syndrome. Reduced expression of Trio in cultured human podocytes decreased basal Rac1 activity, cell size, attachment to laminin, and motility. Furthermore, while the pro-fibrotic cytokine, transforming growth factor β1 increased Rac1 activity in control cells, it decreases Rac1 activity in cells with reduced Trio expression. This was likely due to simultaneous activation of the Rac1-GTPase activation protein, CdGAP. Thus, Trio is important in the basal functions of podocytes and may also contribute to glomerular pathology, such as sclerosis, via Rac1 activation.
肾病综合征是一种以大量蛋白尿为特征的肾脏疾病。它是由肾脏过滤单位（肾小球）内的特化上皮细胞“足细胞”损伤引起的。先前的研究表明，足细胞中 RhoGTPase 的过度激活 Rac1 会导致足细胞损伤和肾小球硬化（肾小球中细胞外基质的积累）。然而，在足细胞损伤过程中 Rac1 如何被激活的机制尚不清楚。Trio 是一种已知能激活 Rac1 的鸟嘌呤核苷酸交换因子（GEF）。通过 RNA 测序，我们发现 Trio mRNA 在培养的人足细胞中大量表达。在微小病变性肾病和局灶节段性肾小球硬化症患者中，Trio mRNA 也显著上调，这两种疾病都是肾病综合征的代表性病因。在培养的人足细胞中降低 Trio 的表达会降低基础 Rac1 活性、细胞大小、与层粘连蛋白的附着和运动性。此外，虽然促纤维化细胞因子转化生长因子β1 会增加对照细胞中的 Rac1 活性，但它会降低 Trio 表达降低的细胞中的 Rac1 活性。这可能是由于 Rac1-GTPase 激活蛋白 CdGAP 的同时激活。因此，Trio 在足细胞的基础功能中很重要，并且可能通过 Rac1 激活也有助于肾小球病变，如硬化。
