Soluble RARRES1 induces podocyte apoptosis to promote glomerular disease progression
Soluble RARRES1 induces podocyte apoptosis to promote glomerular disease progression
复制标题
可溶性 RARRES1 诱导足细胞凋亡促进肾小球疾病进展
DOI：
10.1172/jci140155
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发表时间：
2020-10-01
影响因子：
15.9
通讯作者：
He, John Cijiang
中科院分区：
文献类型：
--
作者：
Chen, Anqun;Feng, Ye;He, John Cijiang
使用肾病综合征研究网络联盟数据集和其他公开可用的转录组学数据集，我们确定了视黄酸受体应答蛋白1（RARRES 1）作为一个基因，其表达与人类肾小球疾病中的肾功能下降呈正相关。在局灶节段性肾小球硬化症（FSGS）和糖尿病肾病（DKD）中，RARRES 1的肾小球表达主要限于足细胞，增加。TNF-α是培养足细胞中RARRES 1表达的有效诱导剂，转录组学分析显示RARRES 1过表达的细胞死亡途径基因富集。RARRES 1的过表达确实在体外诱导足细胞凋亡。值得注意的是，这种作用依赖于其在细胞外结构域中的切割，因为其切割位点的突变消除了凋亡作用。从机制上讲，可溶性RARRES 1被内吞，与RIO激酶1（RIOK 1）相互作用并抑制RIO激酶1，导致p53激活和足细胞凋亡。在小鼠中，足细胞特异性RARRES 1过表达导致显著的肾小球损伤和白蛋白尿，而RARRES 1切割突变体的过表达没有影响。相反，足细胞特异性敲低小鼠中的Rarres 1可改善阿霉素诱导的肾病中的肾小球损伤。我们的研究表明RARRES 1在肾小球疾病足细胞损伤中的重要作用和机制。
Using the Nephrotic Syndrome Study Network Consortium data set and other publicly available transcriptomic data sets, we identified retinoic acid receptor responder protein 1 (RARRES1) as a gene whose expression positively correlated with renal function decline in human glomerular disease. The glomerular expression of RARRES1, which is largely restricted to podocytes, increased in focal segmental glomerulosclerosis (FSGS) and diabetic kidney disease (DKD). TNF-alpha was a potent inducer of RARRES1 expression in cultured podocytes, and transcriptomic analysis showed the enrichment of cell death pathway genes with RARRES1 overexpression. The overexpression of RARRES1 indeed induced podocyte apoptosis in vitro. Notably, this effect was dependent on its cleavage in the extracellular domain, as the mutation of its cleavage site abolished the apoptotic effect. Mechanistically, the soluble RARRES1 was endocytosed and interacted with and inhibited RIO kinase 1 (RIOK1), resulting in p53 activation and podocyte apoptosis. In mice, podocyte-specific overexpression of RARRES1 resulted in marked glomerular injury and albuminuria, while the overexpression of RARRES1 cleavage mutant had no effect. Conversely, podocyte-specific knockdown of Rarres1 in mice ameliorated glomerular injury in the setting of adriamycin-induced nephropathy. Our study demonstrates an important role and the mechanism of RARRES1 in podocyte injury in glomerular disease.