{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T04:43:33Z","timestamp":1771649013546,"version":"3.50.1"},"reference-count":71,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T00:00:00Z","timestamp":1635379200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002301","name":"Estonian Research Council","doi-asserted-by":"publisher","award":["PSG471"],"award-info":[{"award-number":["PSG471"]}],"id":[{"id":"10.13039\/501100002301","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Regional Development Fund (European Union)","award":["Project No. 2014-2020.4.01.15-0012"],"award-info":[{"award-number":["Project No. 2014-2020.4.01.15-0012"]}]},{"name":"CELSA (Central Europe Leuven Strategic Alliance)","award":["Project year 2020"],"award-info":[{"award-number":["Project year 2020"]}]},{"name":"Eye Hope Foundation","award":["-"],"award-info":[{"award-number":["-"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/genes12111717","type":"journal-article","created":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T23:50:28Z","timestamp":1635465028000},"page":"1717","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Expression of RAAS Key Receptors, Agtr2 and Bdkrb1, Is Downregulated at an Early Stage in a Rat Model of Wolfram Syndrome"],"prefix":"10.3390","volume":"12","author":[{"given":"Marite","family":"Punapart","sequence":"first","affiliation":[{"name":"Laboratory Animal Centre, Institute of Biomedicine and Translational Medicine, University of Tartu, 14B Ravila Street, 50411 Tartu, Estonia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6406-7920","authenticated-orcid":false,"given":"Kadri","family":"Seppa","sequence":"additional","affiliation":[{"name":"Laboratory Animal Centre, Institute of Biomedicine and Translational Medicine, University of Tartu, 14B Ravila Street, 50411 Tartu, Estonia"},{"name":"Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, 19 Ravila Street, 50411 Tartu, Estonia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toomas","family":"Jagom\u00e4e","sequence":"additional","affiliation":[{"name":"Laboratory Animal Centre, Institute of Biomedicine and Translational Medicine, University of Tartu, 14B Ravila Street, 50411 Tartu, Estonia"},{"name":"Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, 19 Ravila Street, 50411 Tartu, Estonia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6203-4810","authenticated-orcid":false,"given":"Mailis","family":"Liiv","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, 19 Ravila Street, 50411 Tartu, Estonia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Riin","family":"Reimets","sequence":"additional","affiliation":[{"name":"Laboratory Animal Centre, Institute of Biomedicine and Translational Medicine, University of Tartu, 14B Ravila Street, 50411 Tartu, Estonia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Kirillov","sequence":"additional","affiliation":[{"name":"Laboratory Animal Centre, Institute of Biomedicine and Translational Medicine, University of Tartu, 14B Ravila Street, 50411 Tartu, Estonia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Allen","family":"Kaasik","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, 19 Ravila Street, 50411 Tartu, Estonia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0186-1411","authenticated-orcid":false,"given":"Lieve","family":"Moons","sequence":"additional","affiliation":[{"name":"Research Group Neural Circuit Development and Regeneration, Department of Biology, University of Leuven, Naamsestraat 61, Box 2464, 3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3329-3474","authenticated-orcid":false,"given":"Lies","family":"De Groef","sequence":"additional","affiliation":[{"name":"Research Group Neural Circuit Development and Regeneration, Department of Biology, University of Leuven, Naamsestraat 61, Box 2464, 3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anton","family":"Terasmaa","sequence":"additional","affiliation":[{"name":"Laboratory Animal Centre, Institute of Biomedicine and Translational Medicine, University of Tartu, 14B Ravila Street, 50411 Tartu, Estonia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5226-345X","authenticated-orcid":false,"given":"Eero","family":"Vasar","sequence":"additional","affiliation":[{"name":"Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, 19 Ravila Street, 50411 Tartu, Estonia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mario","family":"Plaas","sequence":"additional","affiliation":[{"name":"Laboratory Animal Centre, Institute of Biomedicine and Translational Medicine, University of Tartu, 14B Ravila Street, 50411 Tartu, Estonia"},{"name":"Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, 19 Ravila Street, 50411 Tartu, Estonia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1136\/jmg.34.10.838","article-title":"Wolfram (DIDMOAD) Syndrome","volume":"34","author":"Barrett","year":"1997","journal-title":"J. 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