Chronic Stress Alters Hippocampal Renin-Angiotensin-Aldosterone System Component Expression in an Aged Rat Model of Wolfram Syndrome. (2023)

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Author(s): Marite Punapart [1]; Riin Reimets [1]; Kadri Seppa [1,2]; Silvia Kirillov [1]; Nayana Gaur [1]; Kattri-Liis Eskla [2]; Toomas Jagomäe [1,2]; Eero Vasar [2]; Mario Plaas (corresponding author) [1,2,*]

1. Introduction

Wolfram syndrome (WS; Appendix A includes a list of abbreviations used) is a rare monogenic neurodegenerative disease caused by biallelic mutations in the gene encoding the transmembrane glycoprotein Wolframin (WFS1). Disease manifestation typically begins with juvenile-onset diabetes mellitus, diabetes insipidus and loss of vision (due to optic nerve atrophy) and is often accompanied by sensorineural deafness and neuropsychiatric abnormalities, among other complications [1,2]. The incidence can vary by ethnicity, ranging from 1/770,000 in the United Kingdom to 1/68,000 in Lebanon, for instance [3,4].

Wfs1 is broadly expressed in several tissues, with higher levels in the brain, pancreas, lungs, heart and retina [5,6,7,8]. WFS1 is primarily involved in regulating Ca[sup.2+] homeostasis and the endoplasmic reticulum (ER) stress response [9,10]. Additionally, Wfs1 deficiency is associated with disruptions in mitochondrial activity, including changes in mitochondrial dynamics and degradation rate [11]. Several unfolded protein response modulators are localized in mitochondria-associated ER membranes (MAMs); these structures facilitate ER-mitochondria interactions that are critical for regulating several functions, including Ca[sup.2+] signaling and metabolism. MAM dysfunction can directly impact cell survival and has been implicated in various metabolic and neurodegenerative disorders. WFS1 also localizes in MAMs, and its absence in fibroblasts results in Ca[sup.2+] exchange disturbances and reduced ER-mitochondria contact formation in vitro [12,13].

While there are currently no curative treatments available for WS, drug-repurposing efforts have identified several promising candidates, including ER stress modulators (e.g., valproate (VPA), originally a first-choice anti-epileptic drug), chemical chaperones (e.g., sigma-1 receptor (S1R) agonists), and antidiabetics (e.g., glucagon-like peptide 1 receptor (GLP-1R) agonists). For instance, S1R agonists restored mitochondrial function and alleviated behavioral deficits in WS animal models [14]. VPA was shown to induce WFS1 expression, modulate the ER stress response and reduce apoptosis in vitro [15,16], as well as ameliorate glucose tolerance in WS mice [17]. Similarly, dantrolene (a skeletal muscle relaxant) suppressed ER stress-mediated cell death in both in vitro and in vivo WS models [18]. VPA and dantrolene are also already being explored in clinical trials (clinical trial identifiers: NCT03717909/NCT04940572 and NCT02829268, respectively; [19]). Interestingly, some drug candidates from across the neurodegenerative spectrum have also demonstrated disease-modifying potential in both in vivo and in vitro WS models. Riluzole, one of the few drugs approved for the treatment of amyotrophic lateral sclerosis (ALS), regulated aberrant glutamate transporter expression in Wfs1-deficient cerebral organoids, thereby restoring synapse formation and functionality. It also improved spatial memory and depressive behavior in Wfs1 conditional knock-out mice [20]. A combination of 4-phenylbutyrate and tauroursodeoxycholic acid, also recently approved in the United States for the treatment of ALS [21], increased WFS1 levels, alleviated ER stress and inhibited cellular apoptosis in patient-derived induced pluripotent stem cells. Moreover, this combination also stimulated insulin secretion in stem cell-derived ß cells and delayed the progression of diabetes in Wfs1-deficient mice [22]. For a comprehensive overview of potential treatment strategies for WS, interested readers may refer to [23].

Antidiabetic GLP-1R agonists in particular have shown promising results by ameliorating disease progression in both rodent models [24,25,26,27,28,29] and human patients [30,31]. More specifically, our group has shown that the GLP-1R agonist liraglutide (LIR) delays the progression of diabetes, loss of vision and neurodegeneration and improves cognitive function in a rat model of WS [24,25,26,27]. An additional trial investigating combination therapy of GLP-1 and glucose-dependent insulinotropic polypeptide receptor agonists will also be underway soon (clinical trial identifier: NCT05659368). However, the mechanisms underlying LIR’s therapeutic effects remain to be elucidated.

Additionally, we have recently shown that the renin-angiotensin-aldosterone system (RAAS) is significantly affected in Wfs1-deficient rats; the expression of two key RAAS receptors, angiotensin II receptor type 2 (Agtr2) and bradykinin receptor B1 (Bdkrb1), was markedly downregulated both in vivo (heart and lungs) and in vitro (in primary cortical neurons). 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].

The RAAS regulates critical functions, including body fluid volume and blood pressure, and its dysregulation is implicated in many conditions, including cancer, diabetes and neurodegenerative disorders [35,36,37]. Importantly, in addition to the “classical” systemic RAAS, tissue-specific “micro-RAASs” have been described for several organs, including the brain and pancreas. These micro-RAASs participate in various cellular processes, including vasodilation and vasoconstriction, proliferation and regeneration and inflammatory responses [38,39,40].

Importantly, the RAAS is also associated with ER stress regulation, mitochondrial functioning and MAMs [41]. Key RAAS components are located in the mitochondria of various tissues, e.g., the adrenal glands, kidneys, liver, heart, and brain (specifically in dopaminergic neurons) [42,43]. To illustrate, redundant angiotensin II, one of the main hormones in the system, increased oxidative stress in microglia and accelerated the apoptosis of dopaminergic neurons [44]. Crucially, modulating the RAAS was shown to alleviate oxidative and ER stress and improve mitochondrial functioning [42,45].

In light of our previous observations and the functional overlap between WFS1 and the RAAS, we wanted to assess whether the RAAS is also altered in the central nervous system (CNS) of WS rats. The brain stem and hippocampus include some of the most notably affected regions in WS [46,47,48]. WFS1 is also highly abundant in these regions, predominating in the CA1 region of the hippocampus and in the brain stem nuclei [5,49].

Accordingly, for the current study, we used hippocampi and brain stem tissue collected as part of our previous long-term treatment study, wherein aged WS rats (9 months) were administered LIR and 7,8-dihydroxyflavone (7,8-DHF, an in vivo brain-derived neurotrophic factor, BDNF, mimetic) for 3.5 months. There, we showed that all treatment modalities (LIR only, 7,8-DHF only or combination) prevented lateral ventricle enlargement, reduced neuroinflammation, delayed optic nerve atrophy and improved visual acuity and learning in WS rats [26]. Therefore, we were additionally interested in evaluating the effect of these drugs on RAAS gene expression. Further, in order to control for stress induced by chronic experimental manipulations, treatment-naïve rats taken directly from their home cages were included as an experimental group.

2. Materials and Methods

2.1. Animals

For this study, outbred male CD[sup.®] (Sprague-Dawley) IGS homozygous Wfs1-deficient (Wfs1-ex5-KO232) rats and their wild-type (WT) littermates (as controls) were used; outbred animals were selected as these are more representative of population-level heterogeneity. Wfs1-ex5-KO232 mutants have previously been extensively characterized [50]. Breeding and genotyping were executed at the Laboratory Animal Centre at the University of Tartu. Animals were housed in groups of 4 under a 12 h light/dark cycle (lights on at 7 a.m.) with unlimited access to food (Sniff universal mouse and rat maintenance diet, Ssniff #V1534, ssniff Spezialdiäten, Germany) and water. All experimental protocols were approved by the Estonian Project Authorization Committee for Animal Experiments (No 155, 6 January 2020), and all experiments were performed in accordance with the European Communities Directive of September 2010 (2010/63/EU). The study was carried out in compliance with the ARRIVE guidelines.

2.2. Treatment and Sample Collection

Nine-month-old animals were randomly allocated to the following treatment groups: liraglutide (LIR, n = 5–7), 7,8-dihydroxyflavone (7,8-DHF, n = 5–7), liraglutide + 7,8-dihydroxyflavone (LIR + 7,8-DHF, n = 6–8) or control (vehicle) group (VEH, n = 5–7). LIR (Novo Nordisk, Denmark) was prepared in 0.9% saline; 7,8-DHF (#D1916, Tokyo Chemical Industry CO., Ltd., Japan) was first dissolved in 100% dimethyl sulfoxide (DMSO) to 400 mg/mL and further diluted 1:20 with a polyethylene glycol-300 (PEG-300)/PBS mix (1:1), resulting in a final solution of 20 mg/mL 7,8-DHF in 5% DMSO/47.5% PEG-300/47.5% PBS. The animals received a daily subcutaneous dose of LIR (0.4 mg/kg), 7,8-DHF (5 mg/kg), LIR + 7,8-DHF or the corresponding vehicle (1 mL/kg for 0.9% saline or 0.25 mL/kg for 5% DMSO/47.5% PEG-300/47.5% PBS) for 3.5 consecutive months [26]. All drug injections were performed between 8 a.m. and 11 a.m.

Of note, the animals also underwent a battery of other experimental manipulations over the study period, including routine blood sugar measurements, visual acuity measurements, cataract scoring, Morris water maze and MRI imaging under isoflurane anesthesia [26].

In order to control for the effect of repeated experimental manipulations, 12.5–13-month-old naïve WS rats and their WT littermates (n = 8, both groups) were used. These animals were not subjected to any treatment or manipulation and were directly euthanized from their home cages.

Both treated (within 24 h following the last injection) and naïve animals (taken directly from their home cages for downstream analyses and hereafter referred to as “treatment-naïve”) were sacrificed by decapitation. The brains were removed, and the hippocampi and brain stems were dissected, immediately washed with 0.9% saline and snap frozen in liquid nitrogen. Tissue samples were stored at -80 °C for further analysis.

2.3. Sample Preparation and Gene Expression Analyses

Hippocampi and brain stems were homogenized (Precellys lysing Kit CK14 + Precellys homogenizer (Bertin Instruments, Montigny-le-Bretonneux, France)), and total RNA from tissue lysates was isolated using Direct-zol RNA MiniPrep (Zymo Research, Irvine, CA, USA) according to the manufacturers’ protocol. Total RNA (500 ng) was reverse-transcribed to cDNA using random hexamers and SuperScript™ III Reverse Transcriptase (Invitrogen, Carlsbad, CA, USA).

qPCR was performed on the QuantStudio 12K Flex Real-Time PCR System (Applied Biosystem, Waltham, MA, USA) using Taqman Gene Expression Mastermix (Thermo Fisher Scientific, Baltics, Vilnius, Lithuania) with the following TaqMan Gene Expression Assays: Ace (angiotensin I converting enzyme; Rn00561094_m1), Ace2 (angiotensin I converting enzyme 2; Rn01416293_m1), Agtr1a (angiotensin II receptor, type 1a; Rn02758772_s1), Agtr1b (angiotensin II receptor, type 1b; Rn02132799_s1), Agtr2 (angiotensin II receptor, type 2; Rn00560677_s1), Bdkrb1 (bradykinin receptor B1; Rn02064589_s1), Bdkrb2 (bradykinin receptor B2; Rn01430057_m1) and Mas1 (MAS1 proto-oncogene G protein-coupled receptor; Rn00562673_s1). The expression of target genes was normalized to Hprt1 (hypoxanthine-guanine phosphoribosyltransferase; Rn01527840_m1) as an endogenous reference control. Relative expression was quantified using the 2[sup.-?Ct] method [50].

2.4. Statistical Analysis

Statistical analyses were performed and data visualized using the GraphPad Prism software v9 (GraphPad Software Inc., San Diego, CA, USA). The data were compared using either a (i) one-way ANOVA followed by Dunnett’s multiple comparisons test or (ii) an unpaired t-test. The data are presented as the mean and standard error of the mean (±SEM). A p-value of <0.05 was considered statistically significant.

3. Results

3.1. Agtr1a, Agtr1b, Agtr2 and Bdkrb1 Levels Are Downregulated in the Hippocampi of WS Rats Receiving Chronic Treatment

The hippocampi of WS rats were analyzed to examine whether the expression of key RAAS components was affected and whether chronic drug treatment with LIR and 7,8-DHF can exert a modulatory effect.

First, hippocampal levels of Agtr1a, Agtr1b, Agtr2 and Bdkrb1 were significantly downregulated in vehicle-treated WS rats relative to their vehicle-treated WT littermates (Figure 1a–d) (p < 0.0001). These alterations were conserved in WS rats across all treatment groups, indicating that none of the administered drugs (LIR only, 7,8-DHF only or combination) were able to modulate this downregulation. In contrast, a treatment-induced effect was evident in WT animals; Agtr1a, Agtr1b, Agtr2 and Bdkrb1 were significantly downregulated across all treatment groups relative to the vehicle group (Figure 1a–d) (p < 0.05). Finally, no significant treatment- or genotype-driven differences were observed for Bdkrb2, Ace, Ace2 and Mas1 expression (Figure 1e–h).

In summary, hippocampal RAAS component expression significantly differed between WS rats and their WT littermates. Surprisingly, chronic drug treatment was unable to influence this difference, although it induced changes in the WT animals.

3.2. RAAS Component Expression Was Unchanged in the Brain Stems of WS Rats Receiving Chronic Treatment

Genotype- and treatment-induced differences in RAAS component expression were also examined in the brain stem. However, in contrast to the observations in the hippocampi, no significant differences for any of the target genes were noted in either between-genotype or between-treatment group comparisons (Figure 2).

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). This suggests that alterations in key RAAS components may be brain region specific.

3.3. Ace, Ace2 and Mas1 Were Significantly Downregulated in the Hippocampi of Treatment-Naïve WS Rats

Several neuropsychiatric complications, including increased anxiety and depression, have been reported in both WS patients and animal models [51]. Moreover, both preclinical and clinical studies have demonstrated a link between RAAS alterations and these complications (for a comprehensive review, see [52]). In lieu of this, it was speculated that chronic treatment- and handling-induced stress may underlie the finding of administered treatments being unable to modulate the downregulated hippocampal levels of Agtr1a, Agtr1b, Agtr2 and Bdkrb1 in vehicle-treated WS rats. It was further hypothesized that fully functional WFS1 is necessary for proper functioning of the RAAS, particularly its compensatory axis, during chronic stress. To investigate this, RAAS component expression was analyzed in age-matched treatment-naïve WS and WT rats taken directly from their home cages.

Indeed, hippocampal RAAS expression in treatment-naïve rats significantly differed relative to their treated counterparts. More specifically, no differences in hippocampal Agtr1a, Agtr1b, Agtr2 and Bdkrb1 expression were noted between treatment-naïve WT and WS rats, in contrast to the finding of these being significantly downregulated in vehicle-treated WS rats. Rather, treatment-naïve WS rats had slightly elevated levels relative to their WT littermates (Figure 3a–d vs. Figure 1a–d). Treatment-naïve WS rats also displayed significantly downregulated Ace, Ace2 and Mas1 levels relative to their treatment-naïve WT littermates (Figure 3f–h) (p < 0.01).

To summarize, hippocampal RAAS expression differed considerably between treated (manipulated) and treatment-naïve (non-manipulated) WS and WT animals, indicating a potential interplay between Wfs1 deficiency and chronic (prolonged treatment- and experiment-induced) stress in RAAS regulation.

3.4. Ace Was Significantly Upregulated and Agtr2 Downregulated in the Brain Stems of Treatment-Naïve WS Rats

The analysis was extended to the brain stems to examine whether RAAS alterations in treatment-naïve rats displayed the same regional specificity as in treated rats.

Indeed, increased Ace and decreased Agtr2 expression was seen in the brain stems of treatment-naïve WS relative to WT rats (Figure 4g,c) (p < 0.05). Additionally, a slight, albeit insignificant, downregulation, was observed for Agtr1a, Agtr1b and Bdkrb1 expression in WS animals (Figure 4a,b,d). Finally, and as observed in the hippocampus, Mas1 and Ace2 expression was also slightly—although not significantly—decreased in WS rats (Figure 4f,h).

Altogether, region-specific differences in treatment-naïve rats were not as pronounced as those observed in treated animals.

4. Discussion

Mutations in a gene encoding WFS1 are the underlying cause of WS. Although WS is a monogenic disorder, pathogenic mechanisms remain poorly understood. Consequently, there is no cure for WS; nevertheless, several promising candidates, including GLP-1R agonists, have been shown to mitigate disease progression. Although this class of drugs was originally designed for the treatment of diabetes, it has demonstrated profound neuroprotective effects in preclinical models of several neurodegenerative conditions, including Alzheimer’s Disease [53], Parkinson’s Disease [54] and stroke [55].

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].

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. The protective functions of AGTR2 have been well established; its stimulation exerts both anti-inflammatory and anti-fibrotic effects and can promote axonal regeneration [56]. In the CNS, AGTR2 activation can induce transactivation of the brain-derived neurotrophic factor (BDNF) receptor tropomyosin receptor kinase B (TrkB), thereby facilitating BDNF/TrkB-mediated signaling. BDNF/TrkB signal transduction can activate several downstream pathways that promote cell proliferation, survival and plasticity. Disruptions in the BDNF/TRKB axis have been implicated in several neuropsychiatric conditions [57].

Both trauma and inflammation have been shown to activate BDKRB1 [58], which subsequently exerts neuroprotective effects by mediating Ca[sup.2+]-dependent bradykinin-induced microglial migration [59]. Taken together, the loss of functional WFS1 may cause disturbances in AGTR2- and BDKRB1-mediated signaling and impair their neuroprotective effects, including cell regeneration, ER stress and inflammatory responses, thereby ultimately exacerbating WS progression. Interestingly, none of the administered treatments were able to rescue the gene downregulation observed in the hippocampi of vehicle-treated WS rats. Conversely, and surprisingly, expression levels were downregulated in WT rats across all treatment groups relative to the vehicle-treated WT rats. We speculate that this phenomenon may result, at least in part, because functional WFS1 is required for these drugs to modulate the RAAS under conditions of prolonged stress caused by long-term experimental manipulation. Additionally, there is a possibility that in WT animals, the neuroprotective potential of these drugs diminishes the need for RAAS engagement, even under chronic stress conditions. Curiously, no significant changes in the RAAS were observed in the brain stems for both between-genotype and between-treatment group comparisons in the treated rats. However, this may indicate that the interplay between WFS1 and the RAAS is influenced by time, region and environmental conditions.

Micro-RAASs can be modulated pharmacologically via cognitive processes, such as learning, as well as by chronic stress [57,60]. This is relevant, since the tissues used in the present study were collected as part of a previous study where animals continuously (3.5 months) underwent several procedures, including drug administration, vision and hearing tests and MRI-based imaging, which undoubtedly induced chronic stress [26]. Considering this and our observation that none of the treatments were able to “normalize” the alterations observed in vehicle-treated WS animals, we speculate that functional WFS1 is required to support the hippocampal RAAS response to chronic stress. Thus, treatment-naïve rats were studied to control for the effects of treatment-induced stress. Indeed, we found that these rats had decreased hippocampal expression of Ace, Ace2 and Mas1, but no changes were observed for Agtr2, Agtr1a, Agtr1b and Bdkrb1, as seen in treated animals. Furthermore, as in treated animals, RAAS alterations in treatment-naïve rats displayed regional specificity when comparing the hippocampi and brain stems.

Decreased levels of hippocampal Ace and Ace2 in treatment-naïve WS rats may indicate disturbances in angiotensin processing and consequently compromised AGTR1-, AGTR2- and MAS1-facilitated signaling. Furthermore, changes in neural ACE and ACE2 activity increase neuronal vulnerability to ER stress and inflammation and facilitate the accumulation of bradykinin and proteins such as tau and amyloid-ß, all of which are implicated in neurodegenerative pathologies [61,62,63,64]. Similarly, ACE inhibition can delay neurodegeneration via the retardation of tau hyperphosphorylation [65], while ACE2 and AGTR2 activation can protect against cognitive impairments [66]. ACE inhibitors may improve cognitive functioning, including learning and memory, by activating the Ang-(1–7)/Mas axis [67]. Interestingly, a recent study found that WFS1-positive neurons in the entorhinal cortex express tau and mediate its shift to the hippocampal CA1 pyramidal cells, leading to a decline in learning and memory [68,69]. Increased vulnerability to tau pathology in WS indicates that, similarly to ACE, WFS1 interacts with tau and mediates its effects [70]. To conclude, the modulation of RAAS components can influence cognitive processes.

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[sup.2+] homeostasis, affect cognition and contribute to the development of neuropsychiatric complications. An interaction between WFS1 and key RAAS components is further supported by their co-expression in various tissues, including the brain, retina, pancreas, heart and lungs (in humans [71]), and their somewhat overlapping roles. WFS1 may potentially affect RAAS regulation under stressful conditions and facilitate the functioning of the system’s stress-response compensatory axis; disturbances in this axis, as seen here, could therefore exacerbate the course of WS disease.

GLP1-R activation can alleviate ER stress and improve cell survival and mitochondrial function via several pathways [72,73], including the ACE2-mediated RAAS compensatory axis: Ace2/Ang-(1–7)/Mas1/Agtr2. This axis supports cellular function and survival via the induction of a strong ER stress response and anti-inflammatory and regenerative pathways [74,75]. Our previous study demonstrated that LIR treatment, in addition to exerting neuroprotective effects and supporting cognitive function, could modulate the RAAS in peripheral organs [32]. Accordingly, we hypothesized that these positive effects may lie downstream of neural RAAS modulation. Here, we found that differentially expressed RAAS genes in the neural tissues of WS animals were not normalized by LIR treatment, suggesting that LIR’s efficacy derives from the modulation of other signaling and/or homeostatic pathways. In the brain, GLP-1Rs are abundant in pyramidal neurons, and their expression is induced by injury in astrocytes and GABAergic interneurons [76,77,78]. Moreover, GLP-1R agonists have been shown to abate microglial activation in vivo in WS rats [25] and increase GABAergic neurotransmission in different disease conditions, including ischemia [78,79]. Interestingly, GABA receptor activation could significantly delay neuronal death in ischemia-induced injury [80]. Accordingly, while the exact mechanisms underlying LIR’s neuroprotective effects in WS remain to be fully elucidated, they may include ameliorating reactive gliosis by modulating GABAergic signalling and/or augmenting ACE2 activity [33].

5. Conclusions

To summarize, the present study showed that the neural RAAS is altered in WS, as evidenced by the substantial changes in the expression of two key receptors, Agtr2 and Bdkrb1. However, those alterations are not conserved across different regions, potentially owing to the differential regional, environmental and temporal modulation of the RAAS across the WS disease course.

Crucially, we showed that those changes vary depending on whether or not animals are exposed to a prolonged stressful environment (long-term animal experimentation), indicating a role played by chronic stress. Stress may further compound the effects of Wfs1 deficiency on RAAS function, and a compromised compensatory axis could ultimately exacerbate the disease process. These results emphasize once more that experimental design and environment can affect gene expression, and that there is a strong need to control for procedural stress and include treatment-naïve animals within experimental paradigms. Finally, we showed that none of the alterations observed in vehicle-treated WS rats were amenable to pharmacological modulation, despite animals experiencing symptomatic improvement in our previous study [26]. This suggests that the neuroprotective effects of these drugs in WS are likely mediated independently of the RAAS.

6. Limitations of the Study

The present study is not without its limitations; alterations were only described at the transcriptomic level, and since protein-level changes were beyond the scope of this study, as it was exploratory, we recommend that future studies address this. Furthermore, experimental tissue samples were harvested from aged rats that had already developed substantial neurological symptoms, including impaired cognitive function and hippocampal lateral ventricle enlargement. Future studies may also consider investigating transcriptomic changes within specific neuronal populations, especially in regions as diverse as the brain stem. Examining the temporal development of RAAS disruptions across the WS disease course also warrants investigation. Finally, the chronic stress conditions described in this study resulted inadvertently from prolonged experimental handling. Additional analyses using classical stress paradigms should be performed to verify the results reported here.

Author Contributions

Conceptualization, M.P. (Mario Plaas); methodology, M.P. (Mario Plaas); formal analysis, M.P. (Mario Plaas), M.P. (Marite Punapart) and K.S.; investigation, K.S., T.J., R.R., K.-L.E. and S.K.; writing—original draft preparation, M.P. (Mario Plaas), M.P. (Marite Punapart) and N.G.; writing—review and editing, M.P. (Mario Plaas), M.P. (Marite Punapart) and E.V.; visualization, M.P. (Marite Punapart) and K.S.; project administration, M.P. (Mario Plaas); funding acquisition, M.P. (Mario Plaas). All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

The study was approved by the Estonian Project Authorization Committee for Animal Experiments (No 155, 6 January 2020), and all experiments were performed in accordance with the European Communities Directive of September 2010 (2010/63/EU). The study was carried out in compliance with the ARRIVE guidelines.

Informed Consent Statement

Not applicable.

Data Availability Statement

The datasets generated and analyzed during this study are available from the corresponding authors on reasonable request.

Conflicts of Interest

The authors declare no conflict of interest.

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Appendix A

List of Abbreviations (in alphabetical order) 7,8-DHF7,8-dihydroxyflavoneAceAngiotensin I converting enzymeAce2Angiotensin I converting enzyme 2Agtr1aAngiotensin II receptor type 1aAgtr1bAngiotensin II receptor type 1bAgtr2Angiotensin II receptor type 2ARRIVEAnimal Research: Reporting of In Vivo ExperimentsBdkrb1Bradykinin receptor B1Bdkrb2Bradykinin receptor B2BDNFBrain-derived neurotrophic factorCNSCentral nervous systemDMSODimethyl sulfoxideEREndoplasmic reticulumGABAGamma-aminobutyric acidGLP-1RGlucagon-like peptide 1 receptorHprt1Hypoxanthine-guanine phosphoribosyltransferaseLIRLiraglutideMAMMitochondria-associated ER membraaneMas1MAS1 proto-oncogene, G protein-coupled receptorPBSPhosphate-buffered salinePEG-300Polyethylene glycol-300RAASRenin-angiotensin-aldosterone systemSEMStandard error of the meanTrkBTropomyosin receptor kinase BVEHVehicleWFS1Wolframin/Wolfram Syndrome 1WSWolfram SyndromeWTWild-type

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Figures

Figure 1: Expression of Agtr1a, Agtr1b, Agtr2 and Bdkrb1 was significantly downregulated in the hippocampi of chronically treated aged Wfs1-deficient rats. Gene expression was analyzed from the hippocampi of 12.5-month-old animals after 3.5 months of treatment with liraglutide (LIR), 7,8-dihydroxyflavone (DHF), liraglutide + 7,8-dihydroxyflavone (LIR + DHF) or vehicle (VEH). Relative gene expression levels of (a) Agtr1a, (b) Agtr1b, (c) Agtr2, (d) Bdkrb1, (e) Bdkrb2, (f) Ace, (g) Ace2 and (h) Mas1 (presented as 2[sup.-?CT] relative to the housekeeper Hprt). Statistical significance was determined using one-way ANOVA followed by Dunnett’s multiple comparisons test * p < 0.05; ** p < 0.01; **** p < 0.0001. The data are presented as mean ± SEM, n = 5–8 per group. [Please download the PDF to view the image]

Figure 2: No significant between-genotype or between-treatment group differences were noted in the brain stems of chronically treated aged Wfs1-deficient rats. Gene expression was analyzed from the brain stems of 12.5-month-old animals after 3.5 months of treatment with liraglutide (LIR), 7,8-dihydroxyflavone (DHF), liraglutide + 7,8-dihydroxyflavone (LIR + DHF) or vehicle (VEH). Relative gene expression levels of (a) Agtr1a, (b) Agtr1b, (c) Agtr2, (d) Bdkrb1, (e) Bdkrb2, (f) Ace, (g) Ace2 and (h) Mas1 (presented as 2[sup.-?CT] relative to the housekeeper Hprt). Statistical significance was determined using one-way ANOVA followed by Dunnett’s multiple comparisons test. The data are presented as mean ± SEM, n = 5–8 per group. [Please download the PDF to view the image]

Figure 3: Expression of Ace, Ace2 and Mas1 was substantially downregulated in the hippocampi of treatment-naïve aged Wfs1-deficient rats. Gene expression was analyzed from the hippocampi of 12.5–13-month-old animals taken directly from their home cages. Relative gene expression levels of (a) Agtr1a, (b) Agtr1b, (c) Agtr2, (d) Bdkrb1, (e) Bdkrb2, (f) Ace, (g) Ace2 and (h) Mas1 (presented as 2[sup.-?CT] relative to the housekeeper Hprt). Statistical significance was determined using an unpaired t-test; ** p < 0.01; *** p < 0.001. The data are presented as mean ± SEM, n = 8 per group. [Please download the PDF to view the image]

Figure 4: Significant upregulation and downregulation of Ace and Agtr2, respectively, was noted in the brain stems of treatment-naïve aged Wfs1-deficient rats. Gene expression was analyzed from the brain stems of 12.5–13-month-old animals taken directly from their home cages. Relative gene expression levels of (a) Agtr1a, (b) Agtr1b, (c) Agtr2, (d) Bdkrb1, (e) Bdkrb2, (f) Ace, (g) Ace2 and (h) Mas1. Gene expression level is presented as 2[sup.-?CT] relative to the housekeeper Hprt. Statistical significance was determined using an unpaired t-test; * p < 0.05 The data are presented as mean ± SEM, n = 8 per group. [Please download the PDF to view the image]

Author Affiliation(s):

[1] Laboratory Animal Centre, Institute of Biomedicine and Translational Medicine, University of Tartu, 14B Ravila Street, 50411 Tartu, Estonia

[2] Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, 19 Ravila Street, 50411 Tartu, Estonia

Author Note(s):

[*] Correspondence: mario.plaas@ut.ee

DOI: 10.3390/genes14040827

COPYRIGHT 2023 MDPI AG
No portion of this article can be reproduced without the express written permission from the copyright holder.

Copyright 2023 Gale, Cengage Learning. All rights reserved.


FAQs

What is the role of the renin-angiotensin-aldosterone system in chronic heart failure? ›

Activity of the renin-angiotensin-aldosterone system (RAAS) is increased in patients with heart failure, and its maladaptive mechanisms may lead to adverse effects such as cardiac remodelling and sympathetic activation. Elevated renin activity has been demonstrated in patients with dilated cardiomyopathy.

Which response in heart failure is triggered by the renin-angiotensin-aldosterone system? ›

Myocardial systolic dysfunction

Activation of the renin-angiotensin-aldosterone system (RAAS) also results in vasoconstriction (angiotensin) and an increase in blood volume, with retention of salt and water (aldosterone).

How does the RAAS system contribute to heart failure? ›

Early in heart failure, RAAS is activated as a compensatory mechanism, but with the progression of the disease, it assumes a detrimental role, responsible for increased preload and afterload, which are the hallmarks of clinical heart failure syndrome.

What happens when RAAS is activated? ›

In particular, activation of the renin-angiotensin-aldosterone system (RAAS) leads to increased levels of angiotensin II and plasma aldosterone, and promote development of arterial vasoconstriction and remodeling, sodium retention, oxidative process, and cardiac fibrosis.

How does the renin-angiotensin system affect the heart? ›

Activated RAAS is an important contributor to changes in arterial and cardiac stiffness, characterized by elevated PWV, increased myocardial stiffness, abnormalities of cardiac diastolic relaxation, and later by hypertension and clinical heart failure.

What is the overall effect of the renin-angiotensin-aldosterone system? ›

The net effects of activation of the RAAS include vasocontriction, increased arterial blood pressure, increased myocardial contractility, sodium and water retention which subsequently increases the effective circulating volume.

What triggers the renin-angiotensin-aldosterone system? ›

Typically, RAAS is activated when there is a drop in blood pressure (reduced blood volume) to increase water and electrolyte reabsorption in the kidney; which compensates for the drop in blood volume, thus increasing blood pressure.

What is the major effect that activating the renin angiotensin pathway causes? ›

It regulates your blood pressure by increasing sodium (salt) reabsorption, water reabsorption (retention) and vascular tone (the degree to which your blood vessels constrict, or narrow).

What is neurohormonal activation in chronic heart failure? ›

In the short-term, these 'neurohormonal' systems induce a number of changes in the heart, kidneys, and vasculature that are designed to maintain cardiovascular homeostasis. However, with chronic activation, these responses result in haemodynamic stress and exert deleterious effects on the heart and the circulation.

How does stress affect the RAAS system? ›

RAAS is one of the most important systems in the development of the pathogenesis of cardiovascular diseases. The activation of RAAS under stress conditions stimulates a series of processes such as oxidative stress related to cardiovascular damage, inflammation and insulin resistance33.

Can a dysfunctional RAAS lead to high blood pressure? ›

Overactivation of the RAAS is also implicated in the development of secondary hypertension due to primary hyperaldosteronism. Primary hyperaldosteronism is the excess aldosterone production either by an adrenal adenoma (Conn syndrome) or bilateral adrenal hyperplasia producing excess aldosterone.

What happens to aldosterone in heart failure? ›

In untreated congestive heart failure, aldosterone plasma concentrations are elevated in proportion to the severity of the disease and are further increased by the use of diuretic treatment. Angiotensin II, plasma potassium concentration, and corticotropin are the major stimulators of aldosterone synthesis.

What happens when RAAS is suppressed? ›

Renal failure and hyperkalemia are the most important complications of suppression of the renin-angiotensin-aldosterone system (RAAS), and an increase in hospital admissions and death from hyperkalemia after publication of the RALES trial illustrates the danger of "casual" use of neurohormonal blockers.

What can happen in human body if RAAS pathway is not working properly? ›

Chronic activation of the renin‐angiotensin‐aldosterone system (RAAS) promotes and perpetuates the syndromes of congestive heart failure, systemic hypertension, and chronic kidney disease.

What is the most significant direct effect of aldosterone release? ›

Aldosterone causes an increase in salt and water reabsorption into the bloodstream from the kidney thereby increasing the blood volume, restoring salt levels and blood pressure.

What are the 4 effects of angiotensin II in the renin-angiotensin system? ›

It causes increases in blood pressure, influences renal tubuli to retain sodium and water, and stimulates aldosterone release from adrenal gland. Besides being a potent vasoconstrictor, Ang II also exerts proliferative, pro-inflammatory and pro-fibrotic activities.

Does renin angiotensin aldosterone increase blood pressure? ›

Aldosterone and vasopressin cause the kidneys to retain sodium (salt). Aldosterone also causes the kidneys to excrete potassium. The increased sodium causes water to be retained, thus increasing blood volume and blood pressure.

What is the overall effect of activation of the renin angiotensin aldosterone pathway quizlet? ›

The renin-angiotensin-aldosterone system supports arterial pressure by causing constriction of arterioles and veins, and retention of water by the kidneys.

What 3 factors stimulate renin secretion? ›

The stimuli to renin release from the juxtaglomerular cells of the kidney are low-renal perfusion pressure, sodium depletion, and hypokalemia, although hyperkalemia acting directly on the zona glomerulosa is a more potent stimulus to aldosterone release than hypokalemia.

What is the most important trigger for aldosterone release in the renin angiotensin? ›

The release of aldosterone from the adrenal glands is regulated via the renin-angiotensin II-aldosterone system. This system is initially activated via a decrease in the mean arterial blood pressure to increase the blood pressure.

What hormones are triggered by renin? ›

Renin activates the renin–angiotensin system by using its endopeptidase activity to cleave the peptide bonds between leucine and valine residues in angiotensinogen, produced by the liver, to yield angiotensin I, which is further converted into angiotensin II by ACE, the angiotensin–converting enzyme primarily within ...

What stimulates renin-angiotensin system in shock? ›

Extracellular fluid volume depletion and/or decreased arterial blood pressure trigger several enzymatic reactions resulting in the release of active renin into surrounding tissues and the systemic circulation.

What are the drugs affecting renin-angiotensin system? ›

RAS-acting agents work by blocking different stages of the renin-angiotensin system (RAS). ARBs (containing the active substances azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan or valsartan) block receptors for a hormone called angiotensin II.

What 2 hormones are released as the body tries to compensate for congestive heart failure? ›

When the body thinks it needs more fluid in its blood vessels, it releases specific chemicals (renin, angiotensin, and aldosterone) that cause the blood vessels to constrict. These hormones also cause the body to hold on to more sodium and water.

What hormone is released during heart failure? ›

ANP and BNP are secreted by the heart and act as cardiac hormones. Human ANP has three molecular forms: α-ANP, β-ANP, and proANP (or γ-ANP). ProANP and β-ANP are minor forms but are increased in patients with heart failure. ProBNP is secreted by the heart and is increased in patients with heart failure.

What is the most common cause of right sided cor pulmonale heart failure? ›

High blood pressure in the arteries of the lungs is called pulmonary hypertension. It is the most common cause of cor pulmonale. In people who have pulmonary hypertension, changes in the small blood vessels inside the lungs can lead to increased blood pressure in the right side of the heart.

Does cortisol activate RAAS? ›

Cortisol Stimulates Tissue RAS and Vice Versa.

Does stress activate RAAS? ›

Psychosocial stress is likely capable of activating the RAAS by the following mechanisms: first, psychosocial stress activates the sympathetic adrenal medullary (SAM) system with consequent release of the catecholamines epinephrine and norepinephrine from the adrenal medulla (13).

Why do individuals with chronic stress often have high blood pressure? ›

The body releases a surge of hormones when under stress. These hormones cause the heart to beat faster and the blood vessels to narrow. These actions increase blood pressure for a time.

Is RAAS activated in congestive heart failure? ›

Chronic heart failure (CHF) is a multi-factorial disease process that is characterized by over activation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system. Both of these systems are chronically activated in CHF.

How does RAAS cause kidney failure? ›

Angiotensin II (AII) is the main effector of the RAAS and exerts its vasoconstrictor effect predominantly on the postglomerular arterioles, thereby increasing the glomerular hydraulic pressure and the ultrafiltration of plasma proteins, effects that may contribute to the onset and progression of chronic renal damage.

What happens to RAAS in kidney failure? ›

The activation of the RAAS system after acute kidney injury triggers renal inflammation and fibrotic process with long-term damaging consequences. To date, there is still a debate on the benefits of RAAS for the kidney in acute settings. Effects of RAAS antagonists are variable in chronic or acute conditions.

What organ does aldosterone affect? ›

A steroid hormone made by the adrenal cortex (the outer layer of the adrenal gland). It helps control the balance of water and salts in the kidney by keeping sodium in and releasing potassium from the body. Too much aldosterone can cause high blood pressure and a build-up of fluid in body tissues.

What are three major effects of aldosterone? ›

High aldosterone symptoms

High blood pressure (hypertension). Headache. Muscle weakness, especially if potassium levels are very low.

What is Conn's syndrome? ›

Conn's syndrome is a hormonal condition in which one or both adrenal glands produce more of the hormone aldosterone than normal. Aldosterone helps balance the levels of salt and potassium in the body and helps control blood pressure. Conn's syndrome causes: high blood pressure (hypertension), which can be quite severe.

Does eating salt increase aldosterone? ›

Conclusions: These results suggest that high salt intake increases aldosterone production and expression of the AT1R mRNA in the cardiovascular tissue in SHRSP, which may contribute to the development of malignant hypertension in salt-loaded SHRSP.

What stimulates RAAS in heart failure? ›

The classical RAAS pathway involves renin secreted by the kidney to produce Ang I from angiotensinogen (derived from the liver) (Figures 1 and 2). Ang I is then converted mainly through ACE to Ang II which predominantly stimulates the AT1 receptor, the major culprit receptor for Ang II-induced cardiovascular pathology.

Does RAAS make heart failure worse? ›

Activity of the renin-angiotensin-aldosterone system (RAAS) is increased in patients with heart failure, and its maladaptive mechanisms may lead to adverse effects such as cardiac remodelling and sympathetic activation.

What happens when RAAS is overactive? ›

The renin-angiotensin-aldosterone system (RAAS) is a major regulatory system of both cardiovascular and renal functions. Overactivity of the RAAS is associated with the development of hypertension, cardiovascular events, and CKD (8 10).

Why is RAAS bad in heart failure? ›

Renin-angiotensin-aldosterone system (RAAS) activation in heart failure with reduced ejection fraction (HFREF) has detrimental long-term effects such as water and salt retention as well as promoting adverse ventricular remodeling.

Does aldosteronism cause weight gain? ›

Aldosterone levels are already elevated in obese individuals (without and adrenal tumor). In fact, aldosterone protects fat. Fat cells can stimulate aldosterone release from adrenal tissue. Thus, with an aldosterone-producing tumor, a vicious cycle of weight gain is created.

What are the symptoms of too much aldosterone? ›

Symptoms
  • High blood pressure.
  • Low level of potassium in the blood.
  • Feeling tired all the time.
  • Headache.
  • Muscle weakness.
  • Numbness.

What stimulates release of cortisol? ›

Adrenocorticotropic hormone (ACTH) is produced by the pituitary gland. Its key function is to stimulate the production and release of cortisol from the cortex (outer part) of the adrenal gland.

What is the role of renin-angiotensin-aldosterone system in relation to cardiovascular diseases and drugs? ›

RAAS mainly acts as a promoter of atherosclerosis by its action on vessels, and by promoting the development of hypertension, insulin resistance and diabetes, obesity, vascular and systemic inflammation.

What is the role of renin-angiotensin-aldosterone system in the heart and lung focus on Covid 19? ›

Moreover, the non-classic RAAS, through the angiotensin-converting enzyme 2 (ACE2), mediates the entry of the etiological agent of COVID-19 (SARS-CoV-2) into cells. This may cause a reduction in ACE2 and an imbalance between angiotensins in favor of AII that may be responsible for the lung and heart damage.

What is the renin-angiotensin-aldosterone system How does it help maintain normal BP? ›

The RAAS is a complex multi-organ endocrine (hormone) system involved in the regulation of blood pressure by balancing fluid and electrolyte levels, as well as regulating vascular resistance & tone. RAAS regulates sodium and water absorption in the kidney thus directly having an impact on systemic blood pressure.

What is the role of the renin-angiotensin-aldosterone system quizlet? ›

The renin angiotensin aldosterone system is a series of reactions designed to help regulate blood pressure. Specialized smooth muscle cells found in the afferent arteriole that sense blood pressure and release rennin.

Which affects the renin-angiotensin-aldosterone system? ›

The increase in sodium in your bloodstream causes water retention. This increases blood volume and blood pressure, thus completing the renin-angiotensin-aldosterone system.

How does the renin-angiotensin-aldosterone mechanism function Why is it controlled by the kidneys? ›

Why is it controlled by the kidneys? The kidneys act as sensors of low blood volume or low blood pressure or decreased renal perfusion that stimulates the renin-angiotensin-aldosterone system is a series of coordinated reactions that help to maintain blood pressure and electrolyte balance in the body.

How does the renin-angiotensin-aldosterone system increase blood pressure? ›

Aldosterone and vasopressin cause the kidneys to retain sodium (salt). Aldosterone also causes the kidneys to excrete potassium. The increased sodium causes water to be retained, thus increasing blood volume and blood pressure.

What controls renin-angiotensin-aldosterone system? ›

The Renin-Angiotensin-Aldosterone System (RAAS) is a hormone system within the body that is essential for the regulation of blood pressure and fluid balance. The system is mainly comprised of the three hormones renin, angiotensin II and aldosterone. Primarily it is regulated by the rate of renal blood flow.

What is the renin-angiotensin system involved in control of secretion of? ›

The renin-angiotensin system has powerful effects in control of the blood pressure and sodium homeostasis. These actions are coordinated through integrated actions in the kidney, cardio-vascular system and the central nervous system.

What does the renin-angiotensin system involved? ›

Renin-angiotensin system is a physiological hormone system involved in the regulation of arterial blood pressure and plasma sodium concentration. When renin is liberated in the blood, it acts on angiotensinogen (a circulating layer), which goes through proteolytic cleavage to make decapeptide angiotensin I.

What is the importance of baroreflex and renin-angiotensin-aldosterone system? ›

Excerpt. The renin-angiotensin-aldosterone system (RAAS) is a critical regulator of blood volume, electrolyte balance, and systemic vascular resistance. While the baroreceptor reflex responds short term to decreased arterial pressure, the RAAS is responsible for acute and chronic alterations.

How does activation of the renin angiotensin system affect electrolyte balance? ›

Activation of the renin-angiotensin system may also cause potassium depletion, which is manifest clinically by a decrease in both total body potassium and serum potassium concentration. These electrolyte disturbances may play a role in the development of ventricular arrhythmias.

What are the stimuli for the activation of the RAAS pathway? ›

Stimuli for the activation of the RAAS pathway include ANSWER: -low blood pressure in arterioles in the nephron, a decrease in fluid flow through the distal tubule, and high blood pressure in the renal artery.

What activates the renin-angiotensin-aldosterone system quizlet? ›

A) Decreased blood volume

Decreased blood volume stimulates the secretion of renin ( because of decreased renal perfusion pressure) and initiates the renin-angiotensin-aldosterone cascade.

What actions of renin lead to increased blood pressure? ›

Renin by itself does not really affect blood pressure. Instead, it floats around and converts angiotensinogen into angiotensin I. Angiotensinogen is a molecule that is primarily produced by the liver and circulates throughout the bloodstream. It is not able to alter the blood pressure as a precursor molecule.

What is the renin-angiotensin-aldosterone system activated in response to quizlet? ›

Reduced blood pressure in the kidneys prompts the juxtaglomerular (JG) cells to release renin, activating the renin-angiotensin-aldosterone system (RAAS).

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