Reichelt-Wurm Simone, Knauss Lena, Strasser Bettina, Scharf Mona, Holler Kathrin, Eggenhofer Elke, Kretz Markus, Banas Bernhard, Banas Miriam C
Department of Nephrology, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany.
Department of Surgery, University Hospital Regensburg, Regensburg, Germany.
Sci Rep. 2025 Jul 30;15(1):27876. doi: 10.1038/s41598-025-12441-5.
The hypoxia-inducible factor 1α (Hif1α) represents the master transcription factor coordinating cellular responses to oxygen depletion. With hundreds of target genes it plays a key role in numerous bio-medical conditions as well as neoplastic and non-cancerous diseases, which in turn requires a strict regulation. Long non-coding RNAs have the potential to virtually control every step of gene expression. We aimed to investigate the expression and role of HIF1A antisense lncRNAs HIF1A-AS1, AS2, and AS3 under hyperglycemic, hypoxic, or both conditions in three non-cancerous human renal cell types: HK-2 cells, primary RPTECs, and mesangial cells. We observed that HIF1A-AS2 and AS3 expression was upregulated under oxygen deprivation. Furthermore, knockdown (KD) of HIF1A-AS3 resulted in a significant reduction of HIF1A-AS2 and even more important of Hif1α in HK-2 cells but not mesangial cells. While KD of HIF1A also had a diminishing effect on HIF1A-AS2 and AS3 RNA levels, KD of HIF1A-AS2 only affected HIF1A-AS3 but not HIF1A. Treating HK-2 cells with Actinomycin D revealed a high HIF1A-AS3 RNA stability. In conclusion, our data reveal a cell-type specific effect of HIF1A-AS3 on HIF1A RNA and protein expression which might allow the development of a cell-type specific HIF1A antagonist based on lncRNAs.
缺氧诱导因子1α（Hif1α）是协调细胞对氧耗竭反应的主要转录因子。它拥有数百个靶基因，在众多生物医学状况以及肿瘤性和非肿瘤性疾病中发挥关键作用，这反过来需要严格调控。长链非编码RNA几乎有可能控制基因表达的每一个步骤。我们旨在研究HIF1A反义长链非编码RNA HIF1A-AS1、AS2和AS3在高血糖、缺氧或两种条件下，在三种非癌性人肾细胞类型（HK-2细胞、原代肾小管上皮细胞和系膜细胞）中的表达及作用。我们观察到在缺氧条件下HIF1A-AS2和AS3的表达上调。此外，在HK-2细胞而非系膜细胞中，敲低（KD）HIF1A-AS3导致HIF1A-AS2显著减少，更重要的是导致Hif1α显著减少。虽然敲低HIF1A对HIF1A-AS2和AS3的RNA水平也有降低作用，但敲低HIF1A-AS2仅影响HIF1A-AS3而不影响HIF1A。用放线菌素D处理HK-2细胞显示HIF1A-AS3的RNA稳定性高。总之，我们的数据揭示了HIF1A-AS3对HIF1A RNA和蛋白质表达的细胞类型特异性作用，这可能有助于基于长链非编码RNA开发细胞类型特异性的HIF1A拮抗剂。
