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

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.

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

“…Taken together, and in agreement with previous observations in the heart and lungs [ 32 ], Agtr1a , Agtr1b , Agtr2 and Bdkrb1 gene expression was substantially downregulated in the hippocampi but not in the brainstems of WS rats relative to their WT littermates exposed to long-lasting treatment. Chronic administration of LIR, 7,8-DHF or their combination induced changes in the hippocampal expression of WT animals but had no significant effect on the expression in the brain stems of either genotype ( Figure 1 vs. Figure 2 ).…”

“…Alterations in hippocampal RAAS component expression in WS animals exposed to prolonged experimental stress were similar to those previously observed in heart, lung and primary cortical neuron cultures [ 32 ]; Agtr2 and Bdkrb1 levels were significantly downregulated relative to WT animals. In addition, the levels of the AGTR1 genes Agtr1a and Agtr1b were also substantially decreased.…”

“…Furthermore, deficient rats had decreased aldosterone and increased bradykinin serum levels, both of which are important hormone modulators of the RAAS. Interestingly, LIR was able to modulate these levels [ 32 ], which is consistent with our previous findings that RAAS components can be pharmacologically modulated by LIR [ 33 , 34 ].…”

“…Present and previous findings indicate that the loss of functional WFS1 might disturb RAAS functioning, as evidenced by alterations in its key components, both peripherally and in the nervous system [ 32 ]. These disturbances may consequently augment oxidative stress, impair inflammatory responses and Ca 2+ homeostasis, affect cognition and contribute to the development of neuropsychiatric complications.…”

“…While the functions of WFS1 remain to be fully understood, our recent study indicated a role in the modulation of the RAAS, as Wfs1 deficiency induced profound alterations in RAAS components both in vivo and in vitro [ 32 ]. Thus, the present study sought to examine (1) the expression of key RAAS components in neural tissues from WS rats and (2) whether any observed alterations can be influenced by LIR (GLP1-R agonist) and 7,8-DHF treatment, both of which have previously demonstrated neuroprotective effects in a rat model of WS [ 26 ].…”