Kruppel-Like Factor 15 Mediates Glucocorticoid-Induced Restoration of Podocyte Differentiation Markers
Kruppel-Like Factor 15 Mediates Glucocorticoid-Induced Restoration of Podocyte Differentiation Markers
复制标题
DOI：
10.1681/asn.2015060672
复制
发表时间：
2017-01-01
影响因子：
13.6
通讯作者：
He, John C.
中科院分区：
文献类型：
--
作者：
Mallipattu, Sandeep K.;Guo, Yiqing;He, John C.
足细胞损伤是原发性肾小球病（如微小病变疾病和原发性FSGS）的诱发事件，糖皮质激素仍然是这些肾小球病的初始且通常是首选的主要治疗方法。由于炎症在这些疾病中并不明显，因此了解糖皮质激素对足细胞的直接作用（独立于免疫调节作用）可能会导致识别糖皮质激素下游的靶点，从而最大限度地减少毒性而不影响疗效。几项研究表明，糖皮质激素治疗可恢复足细胞分化标志物和正常的超微结构，并改善小鼠足细胞的细胞存活。我们以前确定，Kruppel样因子15（KLF15），肾脏富集锌指转录因子，是恢复细胞应激下小鼠和人足细胞的足细胞分化标志物所必需的。在这里，我们表明，在体外治疗与地塞米松诱导KLF15在人类和小鼠足细胞的表达迅速增加，并增强糖皮质激素受体结合到KLF15的启动子区域的亲和力。在三个独立的蛋白尿小鼠模型中，足细胞特异性Klf15的丢失废除了地塞米松诱导的足细胞恢复。此外，KLF15的敲低降低了细胞存活率，并使分化的人足细胞中的肌动蛋白细胞骨架不稳定。相反，KLF15的过表达稳定了人足细胞在细胞应激下的肌动蛋白细胞骨架。最后，在35例微小病变或原发性FSGS患者中，来自人类活检标本的足细胞和肾小球中KLF15表达水平与糖皮质激素反应性相关。因此，这些研究确定了KLF15在介导糖皮质激素在足细胞中的有益作用中的关键作用。
Podocyte injury is the inciting event in primary glomerulopathies, such as minimal change disease and primary FSGS, and glucocorticoids remain the initial and often, the primary treatment of choice for these glomerulopathies. Because inflammation is not readily apparent in these diseases, understanding the direct effects of glucocorticoids on the podocyte, independent of the immunomodulatory effects, may lead to the identification of targets downstream of glucocorticoids that minimize toxicity without compromising efficacy. Several studies showed that treatment with glucocorticoids restores podocyte differentiation markers and normal ultrastructure and improves cell survival in murine podocytes. We previously determined that Kruppel like factor 15 (KLF15), a kidney enriched zincfinger transcription factor, is required for restoring podocyte differentiation markers in mice and human podocytes under cell stress. Here, we show that in vitro treatment with dexamethasone induced a rapid increase of KLF15 expression in human and murine podocytes and enhanced the affinity of glucocorticoid receptor binding to the promoter region of KLF15. In three independent proteinuric murine models, podocytespecific loss of Klf15 abrogated dexamethasone induced podocyte recovery. Furthermore, knockdown of KLF15 reduced cell survival and destabilized the actin cytoskeleton in differentiated human podocytes. Conversely, overexpression of KLF15 stabilized the actin cytoskeleton under cell stress in human podocytes. Finally, the level of KLF15 expression in the podocytes and glomeruli from human biopsy specimens correlated with glucocorticoid responsiveness in 35 patients with minimal change disease or primary FSGS. Thus, these studies identify the critical role of KLF15 in mediating the salutary effects of glucocorticoids in the podocyte.