Retinoic acid receptor responder1 promotes development of glomerular diseases via the Nuclear Factor-κB signaling pathway
Retinoic acid receptor responder1 promotes development of glomerular diseases via the Nuclear Factor-κB signaling pathway
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DOI：
10.1016/j.kint.2021.05.036
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发表时间：
2021-09-20
影响因子：
19.6
通讯作者：
Patrakka, Jaakko
中科院分区：
文献类型：
--
作者：
Moller-Hackbarth, Katja;Dabaghie, Dina;Patrakka, Jaakko
炎症途径在大多数肾小球疾病中被激活，但在肾组织中驱动它们的分子机制尚不清楚。我们在健康肾脏中发现视黄酸受体应答者1 （Rarres1）是一种高度富足谷蛋白。对足细胞特异性敲除动物的研究表明，在肾小球肾炎模型中，Rarres1不需要用于肾小球滤过屏障的正常发育或维持，也不调节肾脏疾病的结局。有趣的是，我们在IgA和糖尿病肾病以及anca相关血管炎患者的肾小球和小管周围毛细血管内皮细胞中检测到Rarres1表达的诱导。对公开可用的RNA数据集的分析表明，诱导Rarres1表达是慢性肾脏疾病的常见分子机制。在内皮细胞中特异性过表达Rarres1的条件敲入小鼠系未显示出任何明显的肾脏表型。然而，在肾小球肾炎模型中，过表达促进了肾损伤的进展。与此一致，内皮细胞中缺乏Rarres1的条件敲除小鼠在疾病模型中得到部分保护。机制上，Rarres1通过激活受体酪氨酸激酶Axl，通过转录因子核因子- κ B信号通路促进炎症和纤维化。因此，内皮细胞中Rarres1表达的诱导是人类肾小球疾病中普遍存在的分子机制，这似乎在通过核因子κ B信号通路驱动炎症和纤维化中具有致病作用。
Inflammatory pathways are activated in most glomerular diseases but molecular mechanisms driving them in kidney tissue are poorly known. We identified retinoic acid receptor responder 1 (Rarres1) as a highly podocyteenriched protein in healthy kidneys. Studies in podocytespecific knockout animals indicated that Rarres1 was not needed for the normal development or maintenance of the glomerulus filtration barrier and did not modulate the outcome of kidney disease in a model of glomerulonephritis. Interestingly, we detected an induction of Rarres1 expression in glomerular and peritubular capillary endothelial cells in IgA and diabetic kidney disease, as well as in ANCA-associated vasculitis. Analysis of publicly available RNA data sets showed that the induction of Rarres1 expression was a common molecular mechanism in chronic kidney diseases. A conditional knock-in mouse line, overexpressing Rarres1 specifically in endothelial cells, did not show any obvious kidney phenotype. However, the overexpression promoted the progression of kidney damage in a model of glomerulonephritis. In line with this, conditional knock-out mice, lacking Rarres1 in endothelial cells, were partially protected in the disease model. Mechanistically, Rarres1 promoted inflammation and fibrosis via transcription factor Nuclear Factor-kappa B signaling pathway by activating receptor tyrosine kinase Axl. Thus, induction of Rarres1 expression in endothelial cells is a prevalent molecular mechanism in human glomerulopathies and this seems to have a pathogenic role in driving inflammation and fibrosis via the Nuclear Factor kappa B signaling pathway.