Department of Biochemistry, School of Medicine, Case Western Reserve University (CWRU) and the Comprehensive Cancer Center of CWRU, Cleveland, Ohio, United States of America.
PLoS One. 2013 Apr 4;8(4):e60213. doi: 10.1371/journal.pone.0060213. Print 2013.
Glomerular podocytes are highly differentiated epithelial cells that are key components of the kidney filtration units. Podocyte damage or loss is the hallmark of nephritic diseases characterized by severe proteinuria. Recent studies implicate that hormones including glucocorticoids (ligand for glucocorticoid receptor) and vitamin D3 (ligand for vitamin D receptor) protect or promote repair of podocytes from injury. In order to elucidate the mechanisms underlying hormone-mediated podocyte-protecting activity from injury, we carried out microarray gene expression studies to identify the target genes and corresponding pathways in response to these hormones during podocyte differentiation. We used immortalized human cultured podocytes (HPCs) as a model system and carried out in vitro differentiation assays followed by dexamethasone (Dex) or vitamin D3 (VD3) treatment. Upon the induction of differentiation, multiple functional categories including cell cycle, organelle dynamics, mitochondrion, apoptosis and cytoskeleton organization were among the most significantly affected. Interestingly, while Dex and VD3 are capable of protecting podocytes from injury, they only share limited target genes and affected pathways. Compared to VD3 treatment, Dex had a broader and greater impact on gene expression profiles. In-depth analyses of Dex altered genes indicate that Dex crosstalks with a broad spectrum of signaling pathways, of which inflammatory responses, cell migration, angiogenesis, NF-κB and TGFβ pathways are predominantly altered. Together, our study provides new information and identifies several new avenues for future investigation of hormone signaling in podocytes.
肾小球足细胞是高度分化的上皮细胞，是肾脏滤过单位的关键组成部分。足细胞损伤或丢失是蛋白尿严重的肾病的标志。最近的研究表明，包括糖皮质激素（糖皮质激素受体的配体）和维生素 D3（维生素 D 受体的配体）在内的激素可以保护或促进足细胞从损伤中修复。为了阐明激素介导的足细胞保护活性的机制，我们进行了微阵列基因表达研究，以确定在足细胞分化过程中这些激素的靶基因和相应途径。我们使用永生化的人培养足细胞（HPCs）作为模型系统，并进行了体外分化实验，然后用地塞米松（Dex）或维生素 D3（VD3）处理。在诱导分化后，包括细胞周期、细胞器动态、线粒体、细胞凋亡和细胞骨架组织在内的多个功能类别受到了最显著的影响。有趣的是，虽然 Dex 和 VD3 能够保护足细胞免受损伤，但它们仅共享有限的靶基因和受影响的途径。与 VD3 治疗相比，Dex 对基因表达谱的影响更为广泛和深远。对 Dex 改变的基因的深入分析表明，Dex 与广泛的信号通路相互作用，其中炎症反应、细胞迁移、血管生成、NF-κB 和 TGFβ 途径发生了主要改变。总之，我们的研究提供了新的信息，并确定了激素信号在足细胞中的未来研究的几个新途径。
