Loss of the androgen receptor suppresses intrarenal calcium oxalate crystals deposition via altering macrophage recruitment/M2 polarization with change of the miR-185-5p/CSF-1 signals
Loss of the androgen receptor suppresses intrarenal calcium oxalate crystals deposition via altering macrophage recruitment/M2 polarization with change of the miR-185-5p/CSF-1 signals
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雄激素受体的丧失通过改变巨噬细胞募集/M2极化以及 miR-185-5p/CSF-1 信号的变化来抑制肾内草酸钙晶体沉积
DOI：
10.1038/s41419-019-1358-y
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发表时间：
2019-03-20
影响因子：
9
通讯作者：
Chang, Chawnshang
中科院分区：
文献类型：
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作者：
Zhu, Wei;Zhao, Zhijian;Chang, Chawnshang
晶体可以引发广泛的肾脏损伤，这可能与肾结石的发展有关。浸润性巨噬细胞可能影响高草酸血症诱导的肾内草酸钙（CaOx）晶体沉积，但其与性激素的联系尚不清楚。本研究表明，抑制肾小管上皮细胞中的雄激素受体（AR）表达可增加巨噬细胞募集/M2极化，从而增强肾内CaOx晶体的吞噬作用。机制解剖提示AR可通过增加miRNA-185-5p表达抑制巨噬细胞集落刺激因子1 （CSF-1）表达，抑制M2极化介导的肾内CaOx晶体吞噬。应用乙醛酸盐诱导的肾内CaOx晶体沉积小鼠模型进行临床前研究发现，与野生型小鼠相比，肾小管特异性AR敲除小鼠的肾内CaOx晶体沉积较少，肾脏内募集的M2巨噬细胞较多。羟基-l-脯氨酸诱导CaOx晶体沉积的体内大鼠模型也表明，ASC-J9®靶向AR通过增加肾巨噬细胞募集/M2极化来抑制肾内CaOx晶体沉积。总之，使用多种体外细胞系和体内小鼠/大鼠模型进行的多项临床前研究结果都表明，用小分子ASC-J9®靶向AR可能通过改变巨噬细胞募集/M2极化来减少肾内CaOx晶体沉积，这是许多肾结石伴高血氧症患者的一个关键表型。
Crystals can trigger a wide range of kidney injuries that may link to the development of kidney stones. Infiltrating macrophages may influence hyperoxaluria-induced intrarenal calcium oxalate (CaOx) crystals deposition, yet their linkage to sex hormones remains unclear. Here we demonstrated that suppressing the androgen receptor (AR) expression in renal tubular epithelial cells increased the macrophage recruitment/M2 polarization that may result in enhancing the phagocytosis of intrarenal CaOx crystals. Mechanism dissection suggested that AR can suppress macrophage colony-stimulating factor 1 (CSF-1) expression via increasing miRNA-185-5p expression to suppress the M2 macrophage polarization-mediated intrarenal CaOx crystals phagocytosis. The preclinical study using glyoxylate-induced intrarenal CaOx crystals deposition mouse model revealed that renal tubule-specific AR knockout mice have less intrarenal CaOx crystals deposition with more recruited M2 macrophages in the kidney compared with the wild-type mice. Results from the in vivo rat model using hydroxy-l-proline-induced CaOx crystals deposition also demonstrated that targeting the AR with ASC-J9® suppressed the intrarenal CaOx crystals deposition via increasing the renal macrophage recruitment/M2 polarization. Together, results from multiple preclinical studies using multiple in vitro cell lines and in vivo mouse/rat models all demonstrated that targeting the AR with a small molecule ASC-J9® may function via altering macrophage recruitment/M2 polarization to decrease the intrarenal CaOx crystals deposition, a key phenotype seen in many kidney stone disease patients with hyperoxaluria.