Rufanova Victoriya A, Lianos Elias, Alexanian Anna, Sorokina Elena, Sharma Mukut, McGinty Ann, Sorokin Andrey
Division of Nephrology and Kidney Disease Center, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Kidney Int. 2009 Jan;75(1):31-40. doi: 10.1038/ki.2008.448. Epub 2008 Sep 10.
The guanine nucleotide exchange factor C3G, along with the CrkII adaptor protein, mediates GTP activation of the small GTPase proteins Rap1 and R-Ras, facilitating their activation of downstream signaling pathways, which had been found to be important in the pathogenesis of glomerulonephritis. We found that expression of C3G protein was upregulated in glomerular epithelial cells in an experimental model of accelerated anti-GBM antibody-induced glomerulonephritis expression. To determine the consequence of its increased expression, we transfected C3G (using adenoviral constructs) into cultured glomerular epithelial cells and measured the activated forms (i.e., GTP-bound) forms of Rap1 and R-Ras. Activation of Rap1 was not affected by C3G; however, the basal level of GTP-bound R-Ras was decreased. Further, C3G over-expression enhanced the activation of R-Ras in response to endothelin. Overexpression of C3G also led to a significant reduction in glomerular epithelial cell spreading and decreased the cells' E-cadherin expression and augmented their migration. We found that C3G was overexpressed in accelerated anti-GBM antibody-induced glomerulonephritis and suggest that this modulates glomerular epithelial cell morphology and behavior.
鸟嘌呤核苷酸交换因子C3G与CrkII衔接蛋白共同介导小GTPase蛋白Rap1和R-Ras的GTP活化，促进其对下游信号通路的激活，而这些下游信号通路已被发现在肾小球肾炎的发病机制中起重要作用。我们发现在加速抗肾小球基底膜（GBM）抗体诱导的肾小球肾炎实验模型中，肾小球上皮细胞中C3G蛋白的表达上调。为了确定其表达增加的后果我们将C3G（使用腺病毒构建体）转染到培养的肾小球上皮细胞中，并测量Rap1和R-Ras的活化形式（即GTP结合形式）。Rap1的活化不受C3G影响；然而，GTP结合的R-Ras的基础水平降低。此外，C3G过表达增强了内皮素刺激下R-Ras的活化。C3G的过表达还导致肾小球上皮细胞铺展显著减少，细胞E-钙黏蛋白表达降低，并增强其迁移能力。我们发现C3G在加速抗GBM抗体诱导的肾小球肾炎中过表达，并表明这会调节肾小球上皮细胞的形态和行为。
