Prevention of kidney fibrosis is an essential requisite for effective therapy in preventing chronic kidney disease (CKD). Here, we identify Old astrocyte specifically induced substance (OASIS)/cAMP responsive element-binding protein 3-like 1 (CREB3l1), a CREB/ATF family transcription factor, as a candidate profibrotic gene that drives the final common pathological step along the fibrotic pathway in CKD. Although microarray data from diseased patient kidneys and fibrotic mouse model kidneys both exhibit OASIS/Creb3l1 upregulation, the pathophysiological roles of OASIS in CKD remains unknown. Immunohistochemistry revealed that OASIS protein was overexpressed in human fibrotic kidney compared with normal kidney. Moreover, OASIS was upregulated in murine fibrotic kidneys, following unilateral ureteral obstruction (UUO), resulting in an increase in the number of OASIS-expressing pathological myofibroblasts. In vitro assays revealed exogenous TGF-β1 increased OASIS expression coincident with fibroblast-to-myofibroblast transition and OASIS contributed to TGF-β1-mediated myofibroblast migration and increased proliferation. Significantly, in vivo kidney fibrosis induced via UUO or ischemia/reperfusion injury was ameliorated by systemic genetic knockout of OASIS, accompanied by reduced myofibroblast proliferation. Microarrays revealed that the transmembrane glycoprotein Bone marrow stromal antigen 2 (Bst2) expression was reduced in OASIS knockout myofibroblasts. Interestingly, a systemic anti-Bst2 blocking antibody approach attenuated kidney fibrosis in normal mice but not in OASIS knockout mice after UUO, signifying Bst2 functions downstream of OASIS. Finally, myofibroblast-restricted OASIS conditional knockouts resulted in resistance to kidney fibrosis. Taken together, OASIS in myofibroblasts promotes kidney fibrosis, at least in part, via increased Bst2 expression. Thus, we have identified and demonstrated that OASIS signaling is a novel regulator of kidney fibrosis.

中文翻译：

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转录因子老星形胶质细胞特异性诱导物质是肾纤维化的新调节因子

预防肾纤维化是有效治疗预防慢性肾病 (CKD) 的必要条件。在这里，我们将老星形胶质细胞特异性诱导物质 (OASIS)/cAMP 反应元件结合蛋白 3 样 1 (CREB3l1)，一种 CREB/ATF 家族转录因子，作为候选促纤维化基因，驱动纤维化的最终共同病理步骤。 CKD 中的通路。尽管来自患病患者肾脏和纤维化小鼠模型肾脏的微阵列数据都显示出 OASIS/Creb3l1 上调，但 OASIS 在 CKD 中的病理生理学作用仍然未知。免疫组织化学显示，与正常肾脏相比，OASIS 蛋白在人纤维化肾脏中过度表达。此外，在单侧输尿管梗阻 (UUO) 后，OASIS 在小鼠纤维化肾脏中上调，导致表达 OASIS 的病理性肌成纤维细胞数量增加。体外测定显示外源性 TGF-β1 增加 OASIS 表达与成纤维细胞向肌成纤维细胞的转变同时发生，OASIS 有助于 TGF-β1 介导的肌成纤维细胞迁移和增殖增加。值得注意的是，通过 OASIS 的全身基因敲除，通过 UUO 或缺血/再灌注损伤诱导的体内肾纤维化得到改善，同时肌成纤维细胞增殖减少。微阵列显示跨膜糖蛋白骨髓基质抗原 2 (Bst2) 表达在 OASIS 敲除肌成纤维细胞中降低。有趣的是，全身性抗 Bst2 阻断抗体方法减轻了正常小鼠的肾纤维化，但在 UUO 后 OASIS 敲除小鼠中没有，这表明 Bst2 在 OASIS 下游发挥作用。最后，肌成纤维细胞限制性 OASIS 条件性敲除导致对肾纤维化的抵抗。总之，肌成纤维细胞中的 OASIS 至少部分通过增加 Bst2 表达来促进肾纤维化。因此，我们已经确定并证明了 OASIS 信号传导是一种新的肾纤维化调节剂。