Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.
Department of Functional Anatomy and Neuroscience, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
FASEB J. 2021 Feb;35(2):e21158. doi: 10.1096/fj.202001820R. Epub 2020 Nov 5.
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.
预防肾纤维化是有效治疗慢性肾脏病 (CKD) 以防止其进展的必要条件。在这里，我们鉴定出星形细胞特异性诱导物质 (OASIS)/cAMP 反应元件结合蛋白 3 样 1 (CREB3l1)，作为一种候选的促纤维化基因，它沿着 CKD 纤维化途径的最终共同病理步骤驱动。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均显示 OASIS/Creb3l1 上调，但 OASIS 在 CKD 中的病理生理作用仍不清楚。免疫组织化学显示，与正常肾脏相比，人类纤维化肾脏中 OASIS 蛋白过度表达。此外，单侧输尿管梗阻 (UUO) 后，小鼠纤维化肾脏中的 OASIS 上调，导致表达 OASIS 的病理性肌成纤维细胞数量增加。体外实验表明，外源性 TGF-β1 增加 OASIS 的表达，同时伴随着成纤维细胞向肌成纤维细胞的转化，并且 OASIS 促进 TGF-β1 介导的肌成纤维细胞迁移和增殖。重要的是，UUO 或缺血/再灌注损伤诱导的体内肾脏纤维化通过系统遗传敲除 OASIS 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) 的表达在 OASIS 敲除肌成纤维细胞中降低。有趣的是，全身性抗-Bst2 阻断抗体方法可减轻正常小鼠的肾脏纤维化，但在 UUO 后的 OASIS 敲除小鼠中则无效，表明 Bst2 在 OASIS 下游发挥作用。最后，肌成纤维细胞特异性 OASIS 条件性敲除导致肾脏纤维化抵抗。总之，肌成纤维细胞中的 OASIS 通过增加 Bst2 的表达促进肾脏纤维化，至少部分如此。因此，我们已经鉴定并证明了 OASIS 信号是肾脏纤维化的一种新的调节因子。
