The injury-induced transcription factor SOX9 alters the expression of LBR, HMGA2, and HIPK3 in the human kidney.

IF 3.7 2区 医学 Q1 PHYSIOLOGY American Journal of Physiology-renal Physiology Pub Date : 2023-01-01 Epub Date: 2022-12-01 DOI:10.1152/ajprenal.00196.2022
Michelle Kha, Krzysztof Krawczyk, Oi Kuan Choong, Francesco De Luca, Gülay Altiparmak, Eva Källberg, Helén Nilsson, Karin Leandersson, Karl Swärd, Martin E Johansson
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引用次数: 1

Abstract

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 (LBR), high mobility group AT-hook 2 (HMGA2), and homeodomain interacting protein kinase 3 (HIPK3) 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.NEW & NOTEWORTHY 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 LBR, HMGA2, and HIPK3 is altered by SOX9 in the kidney tubular epithelium, suggesting the involvement of these gene products in kidney injury and regeneration.

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损伤诱导的转录因子SOX9会改变人类肾脏中LBR、HMGA2和HIPK3的表达。
啮齿类动物肾脏损伤时会诱导 SRY 盒转录因子 9(SOX9),SOX9 阳性细胞会增殖并再生损伤肾脏的近端肾小管。此外,SOX9 阳性细胞还具有向其他肾小管节段分化的能力。在这里,我们描述了 SOX9 在正常和损伤的人类肾脏中的作用。研究发现,在未受伤的肾脏中,SOX9 的表达与一定比例的所谓散在肾小管细胞共定位,而散在肾小管细胞群以前曾被证明参与肾脏损伤和再生。损伤后,在炎症细胞浸润的邻近区域,SOX9 阳性细胞的数量有所增加。利用从人类肾脏组织中提取的原代肾小管上皮细胞(PTECs),SOX9 的表达在培养过程中被自发诱导,并在转化生长因子-β1 的作用下进一步增加,而在干扰素-γ 的作用下被抑制。siRNA 介导的 PTECs SOX9 基因敲除以及差异基因表达、免疫组化表达和荧光素酶启动子分析表明,片层 B 受体(LBR)、高迁移率基团 AT 钩 2(HMGA2)和同源结构域相互作用蛋白激酶 3(HIPK3)可能是 SOX9 的靶基因。此外,研究人员还利用肾脏外植体模型证明,只有SOX9阳性细胞才能在肾脏缺血造成的大规模损伤中存活下来,而且存活下来的SOX9阳性细胞能扩散并重新填充肾小管。我们还利用伤口愈合试验证明,SOX9 能正向调节 PTECs 的迁移能力。这些发现揭示了 SOX9 在人体肾脏损伤和再生过程中激活的功能和调控方面的问题。新近使用小鼠模型进行的研究表明,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,我们发现 SOX9 阳性的细胞代表了未损伤的人类肾脏中散落的肾小管细胞的一部分。此外,我们还发现 SOX9 会改变肾小管上皮细胞中 LBR、HMGA2 和 HIPK3 的表达,这表明这些基因产物参与了肾脏损伤和再生。
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来源期刊
CiteScore
8.40
自引率
7.10%
发文量
154
审稿时长
2-4 weeks
期刊介绍: The American Journal of Physiology - Renal Physiology publishes original manuscripts on timely topics in both basic science and clinical research. Published articles address a broad range of subjects relating to the kidney and urinary tract, and may involve human or animal models, individual cell types, and isolated membrane systems. Also covered are the pathophysiological basis of renal disease processes, regulation of body fluids, and clinical research that provides mechanistic insights. Studies of renal function may be conducted using a wide range of approaches, such as biochemistry, immunology, genetics, mathematical modeling, molecular biology, as well as physiological and clinical methodologies.
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