Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Center for Molecular Pathology, Department of Translational Medicine, Lund University, Malmö, Sweden.
Am J Physiol Renal Physiol. 2023 Jan 1;324(1):F75-F90. doi: 10.1152/ajprenal.00196.2022. Epub 2022 Dec 1.
Induction of SRY box transcription factor 9 (SOX9) has been shown to occur in response to kidney injury in rodents, where SOX9-positive cells proliferate and regenerate the proximal tubules of injured kidneys. Additionally, SOX9-positive cells demonstrate a capacity to differentiate toward other nephron segments. Here, we characterized the role of SOX9 in normal and injured human kidneys. SOX9 expression was found to colocalize with a proportion of so-called scattered tubular cells in the uninjured kidney, a cell population previously shown to be involved in kidney injury and regeneration. Following injury and in areas adjacent to inflammatory cell infiltrates, SOX9-positive cells were increased in number. With the use of primary tubular epithelial cells (PTECs) obtained from human kidney tissue, SOX9 expression was spontaneously induced in culture and further increased by transforming growth factor-β1, whereas it was suppressed by interferon-γ. siRNA-mediated knockdown of SOX9 in PTECs followed by analysis of differential gene expression, immunohistochemical expression, and luciferase promoter assays suggested lamin B receptor (), high mobility group AT-hook 2 (), and homeodomain interacting protein kinase 3 () as possible target genes of SOX9. Moreover, a kidney explant model was used to demonstrate that only SOX9-positive cells survive the massive injury associated with kidney ischemia and that the surviving SOX9-positive cells spread and repopulate the tubules. Using a wound healing assay, we also showed that SOX9 positively regulated the migratory capacity of PTECs. These findings shed light on the functional and regulatory aspects of SOX9 activation in the human kidney during injury and regeneration. Recent studies using murine models have shown that SRY box transcription factor 9 (SOX9) is activated during repair of renal tubular cells. In this study, we showed that SOX9-positive cells represent a proportion of scattered tubular cells found in the uninjured human kidney. Furthermore, we suggest that expression of , , and is altered by SOX9 in the kidney tubular epithelium, suggesting the involvement of these gene products in kidney injury and regeneration.
诱导性 SRY 盒转录因子 9（SOX9）的表达已被证明在啮齿动物的肾损伤中发生，其中 SOX9 阳性细胞增殖并再生受损肾脏的近端小管。此外，SOX9 阳性细胞表现出向其他肾单位分化的能力。在这里，我们描述了 SOX9 在正常和受损人类肾脏中的作用。SOX9 的表达与未受损肾脏中所谓的散在管状细胞的一部分共定位，先前的研究表明该细胞群体参与了肾损伤和再生。在损伤后和炎症细胞浸润的相邻区域，SOX9 阳性细胞的数量增加。使用从人肾组织获得的原代肾小管上皮细胞（PTEC），在培养中 SOX9 的表达自发诱导，并进一步被转化生长因子-β1 增加，而被干扰素-γ 抑制。PTEC 中 SOX9 的 siRNA 介导的敲低，随后进行差异基因表达、免疫组织化学表达和荧光素酶启动子分析，提示核膜蛋白 Lamin B Receptor ()、高迁移率族蛋白 AT 钩 2 () 和同源结构域相互作用蛋白激酶 3 () 可能是 SOX9 的靶基因。此外，还使用肾脏外植体模型证明，只有 SOX9 阳性细胞在与肾缺血相关的大量损伤中存活，并且存活的 SOX9 阳性细胞扩散并重新填充小管。使用伤口愈合测定法，我们还表明 SOX9 正向调节 PTEC 的迁移能力。这些发现揭示了 SOX9 在人类肾脏损伤和再生过程中的激活的功能和调节方面。最近使用鼠模型的研究表明，SRY 盒转录因子 9（SOX9）在肾小管细胞修复过程中被激活。在这项研究中，我们表明 SOX9 阳性细胞代表未受损人类肾脏中发现的散在管状细胞的一部分。此外，我们提出，在肾脏肾小管上皮细胞中， 、 和 的表达被 SOX9 改变，提示这些基因产物参与了肾损伤和再生。
