genes G C A T T A C G G C A T Article The Expression of RAAS Key Receptors, Agtr2 and Bdkrb1, Is Downregulated at an Early Stage in a Rat Model of Wolfram Syndrome Marite Punapart 1, *, Kadri Seppa 1,2 , Toomas Jagomäe 1,2 , Mailis Liiv 3 , Riin Reimets 1 , Silvia Kirillov 1 , Allen Kaasik 3 , Lieve Moons 4 , Lies De Groef 4 , Anton Terasmaa 1 , Eero Vasar 2 and Mario Plaas 1,2, *   Citation: Punapart, M.; Seppa, K.; Jagomäe, T.; Liiv, M.; Reimets, R.; Kirillov, S.; Kaasik, A.; Moons, L.; De Groef, L.; Terasmaa, A.; et al. The Expression of RAAS Key Receptors, Agtr2 and Bdkrb1, Is Downregulated at an Early Stage in a Rat Model of Wolfram Syndrome. Genes 2021, 12, 1717. https://doi.org/10.3390/ genes12111717 Academic Editor: Thangiah Geetha Received: 16 September 2021 Accepted: 27 October 2021 Published: 28 October 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Laboratory Animal Centre, Institute of Biomedicine and Translational Medicine, University of Tartu, 14B Ravila Street, 50411 Tartu, Estonia; kadri.seppa@ut.ee (K.S.); toomas.jagomae@gmail.com (T.J.); riin.reimets@ut.ee (R.R.); silvia.kirillov@ut.ee (S.K.); anton.terasmaa@ut.ee (A.T.) 2 Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, 19 Ravila Street, 50411 Tartu, Estonia; eero.vasar@ut.ee 3 Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, 19 Ravila Street, 50411 Tartu, Estonia; mailis.liiv@ut.ee (M.L.); allen.kaasik@ut.ee (A.K.) 4 Research Group Neural Circuit Development and Regeneration, Department of Biology, University of Leuven, Naamsestraat 61, Box 2464, 3000 Leuven, Belgium; lieve.moons@kuleuven.be (L.M.); lies.degroef@kuleuven.be (L.D.G.) * Correspondence: marite.punapart@ut.ee(M.P.); mario.plaas@ut.ee (M.P.) Abstract: Wolfram syndrome (WS) 1 is a rare monogenic neurodegenerative disorder caused by mutations in the gene encoding WFS1. Knowledge of the pathophysiology of WS is incomplete and to date, there is no treatment available. Here, we describe early deviations in the renin-angiotensin- aldosterone system (RAAS) and bradykinin pathway (kallikrein kinin system, KKS) observed in a rat model of WS (Wfs1 KO) and the modulative effect of glucagon-like peptide-1 receptor agonist liraglutide (LIR) and anti-epileptic drug valproate (VPA), which have been proven effective in delaying WS progression in WS animal models. We found that the expression of key receptors of the RAAS and KKS, Agtr2 and Bdkrb1, were drastically downregulated both in vitro and in vivo at an early stage in a rat model of WS. Moreover, in Wfs1, KO serum aldosterone levels were substantially decreased and bradykinin levels increased compared to WT animals. Neither treatment nor their combination affected the gene expression levels seen in the Wfs1 KO animals. However, all the treatments elevated serum aldosterone and decreased bradykinin in the Wfs1 KO rats, as well as increasing angiotensin II levels independent of genotype. Altogether, our results indicate that Wfs1 deficiency might disturb the normal functioning of RAAS and KKS and that LIR and VPA have the ability to modulate these systems. Keywords: Wolfram syndrome; Wfs1; Wfs1 knock-out; liraglutide; valproic acid; RAAS; aldosterone; bradykinin; Agtr2; Bdkrb1 1. Introduction Wolfram syndrome (WS) is a rare monogenic progressive neurodegenerative disease mainly characterized by juvenile-onset diabetes mellitus, diabetes insipidus, loss of vision due to optic nerve atrophy, sensorineural deafness and retinal ganglion cell death [1,2]. All of these symptoms are also characteristic of the rat model of WS (Wfs1 KO) described by our research group [3]. To date, no treatment is available for WS, although there are some promising drugs against the progression of WS—two of which are the glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide (LIR), used for the treatment of type 2 diabetes [4,5], and mood stabilizer valproic acid (VPA). It has been shown that the GLP-1R agonists LIR and exenatide delay diabetic phenotype in WS rats and mice [6–8] and that dulaglutide Genes 2021, 12, 1717. https://doi.org/10.3390/genes12111717 https://www.mdpi.com/journal/genes