The Expression of RAAS Key Receptors, <i>Agtr2</i> and <i>Bdkrb1</i>, Is Downregulated at an Early Stage in a Rat Model of Wolfram Syndrome

The Expression of RAAS Key Receptors, <i>Agtr2</i> and <i>Bdkrb1</i>, Is Downregulated at an Early Stage in a Rat Model of Wolfram Syndrome

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 (RAA...

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Autores principales: Marite Punapart, Kadri Seppa, Toomas Jagomäe, Mailis Liiv, Riin Reimets, Silvia Kirillov, Allen Kaasik, Lieve Moons, Lies De Groef, Anton Terasmaa, Eero Vasar, Mario Plaas
Formato: article
Lenguaje:EN
Publicado: MDPI AG 2021
Materias:
Wolfram syndrome
<i>Wfs1</i>
<i>Wfs1</i> knock-out
liraglutide
valproic acid
RAAS
Genetics
QH426-470
Acceso en línea:https://doaj.org/article/90b4cfbac9b54ca78c5c3be13cf21805
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spelling oai:doaj.org-article:90b4cfbac9b54ca78c5c3be13cf218052021-11-25T17:41:13ZThe Expression of RAAS Key Receptors, <i>Agtr2</i> and <i>Bdkrb1</i>, Is Downregulated at an Early Stage in a Rat Model of Wolfram Syndrome10.3390/genes121117172073-4425https://doaj.org/article/90b4cfbac9b54ca78c5c3be13cf218052021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4425/12/11/1717https://doaj.org/toc/2073-4425Wolfram 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 (<i>Wfs1</i> 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, <i>Agtr2</i> and <i>Bdkrb1</i>, were drastically downregulated both in vitro and in vivo at an early stage in a rat model of WS. Moreover, in <i>Wfs1</i>, 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 <i>Wfs1</i> KO animals. However, all the treatments elevated serum aldosterone and decreased bradykinin in the <i>Wfs1</i> KO rats, as well as increasing angiotensin II levels independent of genotype. Altogether, our results indicate that <i>Wfs1</i> deficiency might disturb the normal functioning of RAAS and KKS and that LIR and VPA have the ability to modulate these systems.Marite PunapartKadri SeppaToomas JagomäeMailis LiivRiin ReimetsSilvia KirillovAllen KaasikLieve MoonsLies De GroefAnton TerasmaaEero VasarMario PlaasMDPI AGarticleWolfram syndrome<i>Wfs1</i><i>Wfs1</i> knock-outliraglutidevalproic acidRAASGeneticsQH426-470ENGenes, Vol 12, Iss 1717, p 1717 (2021)
institution DOAJ
collection DOAJ
language EN
topic Wolfram syndrome
<i>Wfs1</i>
<i>Wfs1</i> knock-out
liraglutide
valproic acid
RAAS
Genetics
QH426-470
spellingShingle Wolfram syndrome
<i>Wfs1</i>
<i>Wfs1</i> knock-out
liraglutide
valproic acid
RAAS
Genetics
QH426-470
Marite Punapart
Kadri Seppa
Toomas Jagomäe
Mailis Liiv
Riin Reimets
Silvia Kirillov
Allen Kaasik
Lieve Moons
Lies De Groef
Anton Terasmaa
Eero Vasar
Mario Plaas
The Expression of RAAS Key Receptors, <i>Agtr2</i> and <i>Bdkrb1</i>, Is Downregulated at an Early Stage in a Rat Model of Wolfram Syndrome
description 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 (<i>Wfs1</i> 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, <i>Agtr2</i> and <i>Bdkrb1</i>, were drastically downregulated both in vitro and in vivo at an early stage in a rat model of WS. Moreover, in <i>Wfs1</i>, 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 <i>Wfs1</i> KO animals. However, all the treatments elevated serum aldosterone and decreased bradykinin in the <i>Wfs1</i> KO rats, as well as increasing angiotensin II levels independent of genotype. Altogether, our results indicate that <i>Wfs1</i> deficiency might disturb the normal functioning of RAAS and KKS and that LIR and VPA have the ability to modulate these systems.
format article
author Marite Punapart
Kadri Seppa
Toomas Jagomäe
Mailis Liiv
Riin Reimets
Silvia Kirillov
Allen Kaasik
Lieve Moons
Lies De Groef
Anton Terasmaa
Eero Vasar
Mario Plaas
author_facet Marite Punapart
Kadri Seppa
Toomas Jagomäe
Mailis Liiv
Riin Reimets
Silvia Kirillov
Allen Kaasik
Lieve Moons
Lies De Groef
Anton Terasmaa
Eero Vasar
Mario Plaas
author_sort Marite Punapart
title The Expression of RAAS Key Receptors, <i>Agtr2</i> and <i>Bdkrb1</i>, Is Downregulated at an Early Stage in a Rat Model of Wolfram Syndrome
title_short The Expression of RAAS Key Receptors, <i>Agtr2</i> and <i>Bdkrb1</i>, Is Downregulated at an Early Stage in a Rat Model of Wolfram Syndrome
title_full The Expression of RAAS Key Receptors, <i>Agtr2</i> and <i>Bdkrb1</i>, Is Downregulated at an Early Stage in a Rat Model of Wolfram Syndrome
title_fullStr The Expression of RAAS Key Receptors, <i>Agtr2</i> and <i>Bdkrb1</i>, Is Downregulated at an Early Stage in a Rat Model of Wolfram Syndrome
title_full_unstemmed The Expression of RAAS Key Receptors, <i>Agtr2</i> and <i>Bdkrb1</i>, Is Downregulated at an Early Stage in a Rat Model of Wolfram Syndrome
title_sort expression of raas key receptors, <i>agtr2</i> and <i>bdkrb1</i>, is downregulated at an early stage in a rat model of wolfram syndrome
publisher MDPI AG
publishDate 2021
url https://doaj.org/article/90b4cfbac9b54ca78c5c3be13cf21805
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