Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima, Japan.
Division of Molecular Genetics, Shigei Medical Research Institute, 2117 Yamada, Minami-ku, Okayama, Japan.
Sci Rep. 2019 Oct 1;9(1):14101. doi: 10.1038/s41598-019-50685-0.
Tubulointerstitial fibrosis is a progressive process affecting the kidneys, causing renal failure that can be life-threatening. Thus, renal fibrosis has become a serious concern in the ageing population; however, fibrotic development cannot be diagnosed early and assessed noninvasively in both patients and experimental animal models. Here, we found that serum amyloid A3 (Saa3) expression is a potent indicator of early renal fibrosis; we also established in vivo Saa3/C/EBPβ-promoter bioluminescence imaging as a sensitive and specific tool for early detection and visualization of tubulointerstitial fibrosis. Saa3 promoter activity is specifically upregulated in parallel with tumor necrosis factor α (TNF-α) and fibrotic marker collagen I in injured kidneys. C/EBPβ, upregulated in injured kidneys and expressed in tubular epithelial cells, is essential for the increased Saa3 promoter activity in response to TNF-α, suggesting that C/EBPβ plays a crucial role in renal fibrosis development. Our model successfully enabled visualization of the suppressive effects of a citrus flavonoid derivative, glucosyl-hesperidin, on inflammation and fibrosis in kidney disease, indicating that this model could be widely used in exploring therapeutic agents for fibrotic diseases.
肾小管间质纤维化是一种影响肾脏的进行性过程，可导致危及生命的肾衰竭。因此，纤维化的发展已成为老龄化人群中的一个严重问题；然而，在患者和实验动物模型中，纤维化的发展无法早期诊断和进行非侵入性评估。在这里，我们发现血清淀粉样蛋白 A3（Saa3）的表达是早期肾纤维化的一个有力指标；我们还建立了体内 Saa3/C/EBPβ-启动子生物发光成像，作为早期检测和可视化肾小管间质纤维化的敏感和特异性工具。Saa3 启动子活性与肿瘤坏死因子-α（TNF-α）和损伤肾脏中的纤维化标志物胶原 I 平行上调。C/EBPβ 在损伤的肾脏中上调，并在肾小管上皮细胞中表达，对于 TNF-α 诱导的 Saa3 启动子活性的增加是必需的，这表明 C/EBPβ 在肾纤维化发展中起着至关重要的作用。我们的模型成功地可视化了柑橘类黄酮衍生物葡萄糖基橙皮苷对肾脏疾病中炎症和纤维化的抑制作用，表明该模型可广泛用于探索纤维性疾病的治疗药物。
