Laboratory Animal Centre, Institute of Biomedicine and Translational Medicine, University of Tartu, 14B Ravila Street, 50411 Tartu, Estonia.
Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, 19 Ravila Street, 50411 Tartu, Estonia.
Genes (Basel). 2023 Mar 30;14(4):827. doi: 10.3390/genes14040827.
Biallelic mutations in the gene encoding WFS1 underlie the development of Wolfram syndrome (WS), a rare neurodegenerative disorder with no available cure. We have previously shown that deficiency can impair the functioning of the renin-angiotensin-aldosterone system (RAAS). The expression of two key receptors, angiotensin II receptor type 2 () and bradykinin receptor B1 (), was downregulated both in vitro and in vivo across multiple organs in a rat model of WS. Here, we show that the expression of key RAAS components is also dysregulated in neural tissue from aged WS rats and that these alterations are not normalized by pharmacological treatments (liraglutide (LIR), 7,8-dihydroxyflavone (7,8-DHF) or their combination). We found that the expression of angiotensin II receptor type 1a (), angiotensin II receptor type 1b (), and was significantly downregulated in the hippocampus of WS animals that experienced chronic experimental stress. Treatment-naïve WS rats displayed different gene expression patterns, underscoring the effect of prolonged experiment-induced stress. Altogether, we posit that deficiency disturbs RAAS functioning under chronic stressful conditions, thereby exacerbating neurodegeneration in WS.
双等位基因突变导致编码 WFS1 的基因失活，引发 Wolfram 综合征（WS）的发生。WS 是一种罕见的神经退行性疾病，目前尚无有效的治疗方法。我们之前的研究表明，缺乏会损害肾素-血管紧张素-醛固酮系统（RAAS）的功能。在 WS 大鼠模型中，两种关键受体，血管紧张素 II 受体 2（）和缓激肽受体 B1（）的表达在多个器官的体外和体内均下调。在这里，我们表明，RAAS 关键成分的表达在 WS 老年大鼠的神经组织中也失调，而这些改变不能通过药理学治疗（利拉鲁肽（LIR）、7,8-二羟基黄酮（7,8-DHF）或其组合）来正常化。我们发现，在经历慢性实验性应激的 WS 动物的海马体中，血管紧张素 II 受体 1a（）、血管紧张素 II 受体 1b（）和的表达显著下调。未经治疗的 WS 大鼠表现出不同的基因表达模式，这突出了长期实验诱导应激的影响。总之，我们假设缺乏会在慢性应激条件下扰乱 RAAS 的功能，从而加剧 WS 中的神经退行性变。
