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other·preclinical research, neurology, endocrinology, biomedical research·PMC10137641

Chronic Stress Alters Hippocampal Renin-Angiotensin-Aldosterone System Component Expression in an Aged Rat Model of Wolfram Syndrome

Genes · 9 authors, 2 centres

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TL;DR

The findings indicate that neuroprotective drug treatments did not reverse these RAAS alterations.

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Key results showed significant downregulation of *Agtr2* and *Bdkrb1* expression in the hippocampi of vehicle-treated WS rats compared to wild-type, along with decreased *Agtr1a* and *Agtr1b*. Treatment-naïve WS rats exhibited decreased hippocampal *Ace*, *Ace2*, and *Mas1* expression. Critically, none of the administered drug treatments rescued the RAAS gene downregulation observed in the vehicle-treated WS group. Limitations include the transcriptomic-level analysis only and the use of aged rats with established neurological symptoms.

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preclinical research

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ORIGINAL PAPER

PMC10137641

Chronic Stress Alters Hippocampal Renin-Angiotensin-Aldosterone System Component Expression in an Aged Rat Model of Wolfram Syndrome

Genes

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ABSTRACT

Abstract 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 Wfs1 deficiency can impair the functioning of the renin-angiotensin-aldosterone system (RAAS). The expression of two key receptors, angiotensin II receptor type 2 ( Agtr2 ) and bradykinin receptor B1 ( Bdkrb1 ), 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 ( Agtr1a ), angiotensin II receptor type 1b ( Agtr1b ), Agtr2 and Bdkrb1 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 Wfs1 deficiency disturbs RAAS functioning under chronic stressful conditions, thereby exacerbating neurodegeneration in WS. Keywords: Wolfram syndrome; Wfs1 knock-out; GLP1-R agonist; liraglutide; 7,8-DHF; RAAS; Agtr2 ; Bdkrb1

CITATION EXPORT

Marite Punapart, Riin Reimets, Kadri Seppa et al.. Chronic Stress Alters Hippocampal Renin-Angiotensin-Aldosterone System Component Expression in an Aged Rat Model of Wolfram Syndrome. Genes. (2023). https://doi.org/10.3390/genes14040827

AUTHORS

9 · 2 CENTRES

Marite Punapart, Riin Reimets, Kadri Seppa, Silvia Kirillov, Nayana Gaur, Kattri-Liis Eskla, Toomas Jagomäe, Eero Vasar, Mario Plaas

1Laboratory Animal Centre, Institute of Biomedicine and Translational Medicine, University of Tartu, 14B Ravila Street, 50411 Tartu, Estonia
2Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, 19 Ravila Street, 50411 Tartu, Estonia