Re-expression of Sall1 in podocytes protects against adriamycin-induced nephrosis
Re-expression of Sall1 in podocytes protects against adriamycin-induced nephrosis
复制标题
DOI：
10.1038/labinvest.2017.69
复制
发表时间：
2017-11-01
影响因子：
5
通讯作者：
Asanuma, Katsuhiko
中科院分区：
文献类型：
--
作者：
Hosoe-Nagai, Yoshiko;Hidaka, Teruo;Asanuma, Katsuhiko
高度保守的spalt（sal）基因家族成员编码以C2 H2型的多个双锌指基序为特征的蛋白质。人类和小鼠各有四个已知的Sal样基因（人类的SALL 1 -4和小鼠的Sall 1 -4）。已知Sall 1在肾脏发育中起关键作用。为了探索Sall 1在分化足细胞中的意义，我们使用podocin-Cre/loxP系统和siRNA Sall 1敲低（Sall 1 KD）足细胞研究足细胞特异性Sall 1缺陷小鼠（Sall 1 KOpodo/podo）。在生理条件下，Sall 1 KOpodo/podo小鼠在其一生中没有蛋白尿，但在一些足细胞中检测到足突消失。为了阐明Sall 1在受损足细胞中的作用，我们使用阿霉素（ADR）诱导的肾病和肾小球硬化模型。令人惊讶的是，在注射ADR后第14天，对照小鼠中Sall 1的表达升高。在注射ADR后第28天，Sall 1 KOpodo/podo小鼠表现出显著较高的蛋白尿水平和较高数量的肾小球硬化。分化的Sall 1 KD足细胞表现出突触足蛋白的损失，抑制应力纤维的形成，并最终受损的定向细胞迁移。此外，Sall 1的缺失增加了ADR处理后凋亡足细胞的数量。这些结果表明，Sall 1在足细胞中具有保护作用;因此，我们研究了内质网应激标志物GRP 78。ADR处理的Sall 1 KOpodo/podo小鼠中GRP 78表达高于对照小鼠。Sall 1似乎影响受损足细胞中GRP 78的表达。这些结果表明，Sall 1与肌动蛋白重组，内质网应激，并在受损足细胞凋亡。Sall 1在受损足细胞中重新表达的这些保护性方面可能具有减少细胞凋亡和可能的肾小球硬化的潜力。
The highly conserved spalt (sal) gene family members encode proteins characterized by multiple double zinc finger motifs of the C2H2 type. Humans and mice each have four known Sal-like genes (SALL1-4 in humans and Sall1-4 in mice). Sall1 is known to have a crucial role in kidney development. To explore the significance of Sall1 in differentiated podocytes, we investigated podocyte-specific Sall1-deficient mice (Sall1 KOpodo/podo) using a podocin-Cre/loxP system and siRNA Sall1 knockdown (Sall1 KD) podocytes. Under physiological conditions, Sall1 KOpodo/podo mice exhibited no proteinuria during their lifetime, but foot-process effacement was detected in some of the podocytes. To elucidate the role of Sall1 in injured podocytes, we used an adriamycin (ADR)-induced model of nephrosis and glomerulosclerosis. Surprisingly, the expression of Sall1 was elevated in control mice on day 14 after ADR injection. On day 28 after ADR injection, Sall1 KOpodo/podo mice exhibited significantly higher levels of proteinuria and higher numbers of sclerotic glomeruli. Differentiated Sall1 KD podocytes showed a loss of synaptopodin, suppressed stress fiber formation, and, ultimately, impaired directed cell migration. In addition, the loss of Sall1 increased the number of apoptotic podocytes following ADR treatment. These results indicated that Sall1 has a protective role in podocytes; thus, we investigated the endoplasmic reticulum stress marker GRP78. GRP78 expression was higher in ADR-treated Sall1 KOpodo/podo mice than in control mice. Sall1 appeared to influence the expression of GRP78 in injured podocytes. These results suggest that Sall1 is associated with actin reorganization, endoplasmic reticulum stress, and apoptosis in injured podocytes. These protective aspects of Sall1 re-expression in injured podocytes may have the potential to reduce apoptosis and possibly glomerulosclerosis.