Department of Urology and Guangdong Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, 510230, Guangzhou, China.
George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology, and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, 14646, USA.
Cell Death Dis. 2019 Mar 20;10(4):275. doi: 10.1038/s41419-019-1358-y.
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.
晶体可引发广泛的肾脏损伤，可能与肾结石的发生有关。浸润的巨噬细胞可能影响高草酸尿诱导的肾内草酸钙（CaOx）晶体沉积，但它们与性激素的联系尚不清楚。在这里，我们证明抑制肾小管上皮细胞中的雄激素受体（AR）表达会增加巨噬细胞募集/M2 极化，从而增强肾内 CaOx 晶体的吞噬作用。机制分析表明，AR 可以通过增加 miRNA-185-5p 的表达来抑制巨噬细胞集落刺激因子 1（CSF-1）的表达，从而抑制 M2 巨噬细胞极化介导的肾内 CaOx 晶体吞噬作用。使用乙醛酸诱导的肾内 CaOx 晶体沉积小鼠模型进行的临床前研究表明，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，肾脏中募集的 M2 巨噬细胞较多。使用羟基-L-脯氨酸诱导的 CaOx 晶体沉积的体内大鼠模型的结果也表明，用 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均表明，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，这是许多高草酸尿症肾结石病患者的一个关键表型。
