Mechanisms of angiotensin II to induce depression in diabetes

Abstract

The expression of angiotensin II (Ang II) has been reported in diabetes associated with hypertension and inflammatory processes. It has also been reported a link between Ang II, depression and diabetes; however, underlying mechanisms of Ang II-induced depression in this disease remain unclear. This review focuses on the possible mechanisms of Ang II to induce depression in diabetes. Ang II can induce pro-inflammatory events that activate indoleamine 2,3-dioxygenase and kynurenine monooxygenase. These activated enzymes act by decreasing the production of serotonin and increasing the production of quinolinic acid which acts on the N-methyl-d-aspartate receptor and the amino-methyl propionic acid receptor inducing decreased brain-derived neurotrophic factor (BDNF) expression and depression. Ang II can also induce the production of galectin 3 which has a depressant effect. Neuroinflammation induced by Ang II during diabetes can alter brain cells, event associated with functional disorders and depression. Furthermore, Ang II is capable of inducing oxidative stress in diabetes linked to depressive behaviors. In conclusion, Ang II has the potential to induce depression during diabetes through different mechanisms that involve inflammatory processes, oxidative stress, the production of galectin 3, and decrease in serotonin and BDNF. These findings open the possibility of using anti-Ang II drugs for the treatment of depressive behavior in diabetes.

Introduction

Diabetes mellitus (DM) is one of the most widespread chronic diseases in the world [1]. Depression is also a highly widespread disorder that exacerbates other illnesses, increasing morbidity, mortality, and decreasing quality of life [2, 3]. Both diseases frequently co-occur, with depression influencing the progression of diabetes [4–7]. Depression has been linked to the inflammatory events observed in diabetes [8–10] and angiotensin II (Ang II), a molecule with pro-inflammatory properties, has been associated with diabetes [9, 11–18] and depressive behavior [19, 20]. In this regard, Ang II AT1 receptor antagonists or Ang II synthesis blockers reduce hypothalamic–pituitary–adrenal axis activity and depression in patients with type 2 diabetes [21]. Experimental studies report decreased retinopathy, reduced inflammatory response in the hippocampus, and decreased depression in rats with diabetes treated with anti-Ang II drugs [22, 23]. These studies suggested a connection between Ang II blockers and reduction of depressive symptoms in diabetes although underlying mechanisms of Ang II-induced depression remain unclear. The aim of this review is to emphasize the possible mechanisms of Ang II to induce depression during diabetes.

Depression in diabetes

Previous clinical studies have reported the association of depressive behavior in patients with diabetes. Depression occurs in both types 1 and 2 diabetes, expressing as either major depression or minor depression [24–28]. The association of diabetes with depression has a bidirectional nature, where the patient with diabetes can develop depression and patients with depression can develop diabetes [25–27]. In this context, the diagnosis of diabetes represents a risk of depression due to alterations in the autonomic and neurohormonal nervous system, accompanied by inflammatory processes and alterations in the hippocampus [28]. Approximately 20% to 30% of patients with diabetes present depressive behavior of varying intensity [24, 26], that causes a persistent feeling of sadness and loss of interest, leading to a reduction in disability-adjusted life years and complications of diabetes due to poor therapy adherence [26, 29].

Angiotensin II overview

Angiotensin II (Ang II) is an octapeptide which belongs to renin–angiotensin system (RAS) recognized as a cardiovascular circulation hormonal system. This system is found in various organs, including the brain its main effector being Ang II [30]. Angiotensin II is produced through cleavages of renin forming Ang I, which is then converted to Ang II by angiotensin-converting enzyme 1 (ACE 1). This conversion to Ang II involves the RAS pathway mediated by ACE; however, the non-RAS pathway (Cathepsin D, Cathepsin G, Chymase) can also contribute to Ang II production [11]. Angiotensin-converting enzyme 2 (ACE2) is another carboxypeptidase that removes one amino acid from Ang II leading to the production of the heptapeptide vasodilatory Ang 1–7. The balance between ACE1 and ACE2 is crucial for controlling Ang II levels [13, 31]. Other aminopeptidases can cleave Ang II and generate Ang III (2–8) and Ang IV (3–8). Angiotensin III has similar effects to Ang II albeit with lower potency [17, 32] (Fig. 1). Additionally, a functional intracellular RAS has been identified. The presence of local and intracellular RAS suggests autocrine and apocrine effects of Ang II in various tissues including pro-inflammatory, proliferative, and pro-fibrotic activities leading to tissue injury [33, 34].

Fig. 1.

Renin–angiotensin system. The angiotensinogen is transformed into Ang I by the action of the enzyme renin. Ang I is transformed into Ang II by the action of ACE 1, cathepsins D and G or by chymase. In addition to, Ang I can be converted into Ang 1–9 by ACE2 that under the action of ACE 1, it gets converted into Ang 1–7. Ang II can also be converted into Ang 1–7 by ACE2 which under the action of ACE 1 can be transformed into Ang 1–5. Various aminopeptidases can act on Ang II to produce Ang 2–8 and Ang 3–8. ACE 1: angiotensin-converting enzyme 1; ACE 2: angiotensin-converting enzyme 2; DAP I–III: Dipeptidyl-aminopeptidase I-III; APA: aminopeptidase A; APN: aminopeptidase N; Ang I: angiotensin I; Ang II: angiotensin II; Ang 1–5: angiotensin 1–5; Ang 1–7: angiotensin 1–7; Ang 1–9: angiotensin 1–9; Ang 2–8: angiotensin 2–8; Ang 3–8: angiotensin 3–8

Angiotensin II acts through two distinct G protein-coupled receptors, namely the angiotensin type 1 (AT1, isoforms A and B) and the type 2 (AT2) receptors [14, 35]. AT1A confers Ang II actions, such as increase blood pressure [36], retaining salt in proximal tubular cells [37], release aldosterone [38], and stimulating the sympathetic nervous system in the brain [39]. Angiotensin II also activates the AT1 receptor to induce pro-inflammatory, vasoconstrictive, and fibrotic effects [40, 41]. The AT2 receptor induces vasodilation and improves arterial remodeling, and it is upregulated during cardiovascular injury [42].

As such, Ang II initiates the activation of an inflammatory process that includes increased oxidative stress, and production of cytokines, chemokines, and growth factors mediated by the activation of the transcription factor NF-κB [11, 41]. Local activation of RAS and Ang II synthesis increases vascular permeability mediated by the secretion of vascular endothelial growth factor (VEGF) [43, 44] and increased expression of endothelial adhesion molecules and their ligands [45, 46], and specific cytokine/chemokines expression [47, 48] favoring the recruitment of infiltrating inflammatory cells into tissues. Angiotensin II also promotes endothelial dysfunction through the cyclooxygenase 2 (COX-2) activation, generating vasoactive prostaglandins and reactive oxygen species (ROS) that promote mitochondrial dysfunction [49, 50]. Furthermore, a pro-fibrotic effect of Ang II mediated by elaboration of TGF-beta 1, a fibrogenic cytokine responsible for connective tissue formation and tissue deterioration, has been reported [51]. Therefore, Ang II promotes inflammation and tissue injury through the AT1R activation (Fig. 2). The autocrine regulation of the local angiotensin system involves the co-expression of Ang II receptors (AT1 and AT2) and Ang 1–7 receptors (Mas). Activation of the Mas receptor by Ang 1–7 produces effects opposite to those observed in Ang II by activation of PI3K/Akt and inhibition of MAPK kinase/ERK pathways [52].

Fig. 2.

Effects of Angiotensin II. Angiotensin II (Ang II) has various effects on the body. It can induce inflammation through the interaction with its AT1 receptor and with the nuclear translocation of NF-kB factor, inducing various pro-inflammatory cytokines, oxidative stress and other soluble factors. This activation of Ang II can induce endothelial dysfunction mediated by molecules that act directly or indirectly on the endothelial cell, with the consequent increase in vascular permeability and plasma leakage. This hormone has a vasopressor effect mediated by several mechanisms that include direct effect of the hormone, endothelin I production, effect on the sympathetic nervous system (SNS), activation of cyclooxygenase 2 (COX-2), induction of cytokines, among other molecules. The ability of Ang II to induce fibrosis by activating oxidative stress and production of TGF-beta 1, a fibrogenic cytokine responsible for connective tissue formation and tissue deterioration, has also been reported. ROS (reactive oxygen species); TGF-beta 1 (transforming growth factor beta 1); VEGF (vascular endothelial growth factor); VCAM-1 (vascular cell adhesion molecule 1); ICAM-1 (intercellular adhesion molecule 1)

Angiotensin II has been implicated in damage to various organs and systems. The imbalance between increased Ang II and the ACE2/Ang 1–7/Mas receptor axis contributes to renal injury. In this context, increased Ang II, by altering renal hemodynamics, contributes to hyperfiltration, glomerulomegaly, and subsequent focal glomerulosclerosis [53, 54]. This hormone has also been implicated in the increased retention of renal sodium, leading to hypertension. Increased Ang II production increases tumor growth factor beta (TGF-β) and plasminogen activator inhibitor-1 (PAI-1) expressions, inducing glomerular fibrosis [55]. Renal abnormalities induced by Ang II may also be linked to the effects of oxidative stress on the large-conductance, calcium (Ca²⁺)-activated potassium (K⁺) channels in podocytes. Additionally, Ang II induces podocyte apoptosis [56].

Angiotensin II is also capable of inducing cardiac and arterial damage. This hormone may play a role in modulating both intracardiac lipid content and lipid metabolism-related gene expression, partially via AT1 receptor-dependent and pressure-independent mechanism [57]. Angiotensin II and catecholamines may induce increased levels of G protein-coupled receptor kinase 2 (GRK2) in various cardiovascular cell types. This could explain the contribution of increased GRK2 levels to altered cardiovascular function and remodeling [58]. Lipid accumulation in the heart may play a significant role in the pathogenesis of heart failure. Myocyte steatosis can amplify the fibrotic effects of Ang II through the activation of TGF-β signaling and increased production of ROS [59]. Atherosclerosis is a complex, chronic disease typically arising from the converging action of several pathogenic processes, including obesity, hypertension, hyperlipidemia, and insulin resistance. The capacity of Ang II to induce atherosclerosis and cardiovascular damage has been reported in both human and animal studies [60]. Despite the harmful effects of Ang II on the heart, some of its metabolites (Ang 1–7) may have beneficial cardiovascular and metabolic effects when Ang 1–7 interacts with the Mas receptor [61].

Angiotensin II represents a significant risk factor for hypertension [62]. Elevated levels of circulating leptin can increase sympathetic nerve activity and raise blood pressure. Leptin-induced hypertension is mediated by the up-regulation of central RAS and pro-inflammatory cytokines [63]. Angiotensin II is also capable of suppressing AMPK activity in the kidney, leading to sodium retention, enhanced salt sensitivity, and hypertension [64]. Vitamin D deficiency has been associated with increased vascular sensitivity to Ang II leading to hypertension [65].

Angiotensin II may also impact the fibrinolytic system. The inhibition of fibrinolysis associated with increased plasminogen activator inhibitor 1 (PAI-1) has been documented [66]. PAI-1 is the primary main inhibitor of the fibrinolytic system and was recently shown to be produced by adipose cells. Angiotensin II and its metabolites promote PAI-1 production and release by human adipocytes, potentially contributing to the impairment of the fibrinolytic system. AT1 receptor blockade reduces Ang II-stimulated PAI-1 release from human adipocytes [66].

As deduced from these data, imbalance of Ang II production has diverse and distinct effects on the body ranging from induction of inflammatory processes to biochemical alterations in various systems. This underscores the significance of this hormone as a crucial factor to consider when studying its role in certain pathological processes.

Renin–angiotensin system in central nervous system

Initially, the RAS was identified in the kidney, where it was recognized to be involved in blood pressure regulation and kidney-mediated fluid homeostasis [67]. However, the presence of RAS has been detected in various organs, including the central nervous system (CNS) [30]. All the components of RAS have been identified within the brain, encompassing Ang II [68–70], other peptide derivatives, such as Ang 1–7, various types of Ang receptors including AT1R, AT2R, AT3R, AT4R, MasR [71–74], angiotensin I-converting enzyme (ACE 1), and angiotensin II-converting enzyme (ACE 2) [75]. Actions derived from the interaction between these receptors and their ligands lead to either neurotoxicity or neuroprotection. The ACE/Ang II/AT1R axis is associated with neuronal damage, whereas the ACE/Ang II/AT2R and the ACE2/Ang 1–7/MasR axes confer protective effects [76]. The ACE/Ang II/AT1R axis predominantly mediates Ang II actions within both the central and the peripheral nervous systems [77]. This axis involves the production of pro-inflammatory cytokines [78], activation of the NADPH–oxidase complex and microglial induction of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) [79–81], which are significant events in neurodegenerative disorders and the regulation of the hypothalamic–pituitary–adrenal axis [82, 83]. In this context, AT1R blockade in humans downregulates this axis [84]. AT1R is prominently present in the anterior pituitary and hypothalamus, and its overstimulation leads to endothelial dysfunction and neuronal damage [85–87]. AT2R is abundant in the amygdala, caudate putamen, medial geniculate body, globus pallidus, habenula, hypoglossal nucleus, inferior colliculus, inferior olivary nucleus, locus coeruleus, thalamus, and ventral tegmental area [30]. MasR is broadly expressed in the brain, and its interaction with Ang 1–7 triggers arachidonic acid production and activates iNOS [88, 89]. Although the presence of the RAS components in the CNS is established, their origin remains a subject of controversy [90–92].

Angiotensin II, serotonin (5HT) and brain-derived neurotrophic factor (BDNF) in the central nervous system during diabetes

Angiotensin II acts on the brain to produce a variety of effects including elevation of arterial blood pressure, increased release of vasopressin and ACTH, stimulation of drinking and sodium appetite, and natriuresis [93]. It has been shown that during diabetes, all RAS components are overexpressed in the central nervous system [93–99]. One of the potentially harmful elements that may cause neurological impairments in the brain is diabetes-related activation of the RAS. Activation of Ang II in the brain during diabetes occurs through several pathways, observed in other locations of Ang II. The profound effects of the intrinsic Ang II generated within the brain are mediated by ACE/Ang II/AT1R axis [93–98]. Previously, it was discovered that the AT1R is expressed in several brain areas, including the hypothalamus [100–102]. Previous studies report that insufficient endogenous Ang 1–7 in the brain caused diabetes-induced alterations in hypertensive and diabetic rats [103–105]. Some pathophysiological processes associated with brain RAS-induced diabetes encephalopathy include higher levels of oxidative stress, inflammation, apoptosis, and endothelial dysfunction [105–108]. It is important to know how the brain’s RAS is controlled in both normal and pathological conditions to better understand how the major RAS components are expressed and activated in the brain. In the case of diabetic–hypertensive situations, the over activation of the Ang II/AT1R axis while the lowered level of the protective axis through the MAS receptor may cause neuronal injury in the brain [96, 104]. NF-κB modulates inflammation and the immune system at the brain cellular level in the activation of Ang II during diabetes [109–111]. Experimentally, it has been shown that during diabetes, the RAS system is overactivated with negative consequences in the cerebral cortex, accompanied by overstimulation of the ACE/ Chymase/Ang II/ ATR1 pathway and decreased signaling through the ACE2/Ang 1–7/ Mas receptor pathway with the consequent induction of oxidative stress, apoptosis and inflammation [112]. Other studies have shown in brain and cerebellum of diabetic rats the expression of Ang II accompanied by the induction of pro-inflammatory elements, such as leukocyte infiltration, increased expression of adhesion molecules (ICAM-1, LFA-1), and oxidative stress [9].

According to the monoamine theory, 5HT (serotonin) is the main neurotransmitter that is reduced in depression [113]. A broader explanation of the relationship serotonin, diabetes and Ang II will be described in the section “Angiotensin II in the central nervous system and depression”. It has been revealed that Ang II can inhibit synthesis and release of 5HT in the hippocampus during diabetes [114]. In addition, Ang II increases the turnover and metabolism of 5HT as evidenced by an increase in its metabolite 5HIAA [114]. AT1R blockade modulates 5HT metabolism [114]. ACE2 metabolizes Ang II to Ang1–7 and is essential for the intestinal uptake of tryptophan (Trp), the 5HT precursor, and depletion of ACE2 reduces brain serotonin [115]. Induction of ACE2 promotes the increase of brain serotonin through the ACE2/Ang (1–7)/MAS receptor pathway suggesting the anti-serotonin effect of Ang II [116]. Therefore, inhibition of central classical RAS by ARBS and ACE1s prevents the development of depression by regulating 5HT, BDNF, mitochondrial dysfunction, oxidative stress, and neuroinflammation [117]. Thus, inhibition of the classical RAS pathway by ARBs and ACEIs mitigates brain 5HT biosynthesis (Fig. 3).

Fig. 3.

Depressant and antidepressant effects of RAS on the central nervous system. Angiotensin II (Ang II) can inhibit synthesis and release of 5HT in the hippocampus during diabetes. In addition, Ang II increases the turnover and the metabolism of 5HT as evidenced by an increase in its metabolite 5HIAA, effects mediated by AT1R activation. ACE2 metabolizes Ang II to Ang1–7 promoting the increase of brain serotonin (5HT) through the ACE2/Ang (1–7)/MAS receptor pathway with anti-depressant effect due to decreased expression of Ang II. Therefore, inhibition of central classical RAS by ARBS (antagonists of AT1R) and ACE1 (inducer of Ang II synthesis) prevents the development of depression by regulating 5HT, BDNF, mitochondrial dysfunction, oxidative stress, and neuroinflammation. RAS: renin–angiotensin system; 5HT: 5-hydroxytryptamine; ACE1: angiotensin-converting enzyme 1; ACE2: angiotensin-converting enzyme 2; BDNF: brain-derived neurotrophic factor; ⊢: inhibitory effect

BDNF is a member of the neurotrophins protein family that is concerned with neuronal injury resistance [118]. BDNF is released from peripheral tissues and the central nervous system, mostly hypothalamus, hippocampus, and limbic system [119]. BDNF/TrkB signaling is essential for hippocampal long-term potentiation via activation of extracellular signal-regulated protein kinase (ERK) and mitogen-activated protein kinase (MAPK) [120]. Inhibition of AT1R decreases BDNF/TrkB activity in astrocytes [20]. Furthermore, it has been observed that Ang II reduced BDNF expression by inducing the expression of toll-like receptor 4 (TLR4) and pro-inflammatory NF-κB [121]. Likewise, administration of the AT1 receptor antagonist valsartan promotes neurogenesis via a BDNF-dependent pathway in mice [122]. Therefore, the inhibition of the central ACE1 and AT1R increases BDNF expression [123]. Several experimental studies showed that activation of the Ang1–7/MASR axis promotes expression of the BDNF/TrkB axis [124, 125]. These observations propose that dysregulation of central RAS may reduce the expression and the functional activity of the BDNF/TrkB axis. These findings support the link between diabetes comorbid depression, inflammation and repressed BDNF signaling. RAS could provide new therapeutic options to improve the outcomes of both disorders [23].

Angiotensin II in the central nervous system and depression.

The activity of the renin–angiotensin system in the CNS is linked to the onset of depression. In this context, the activation of the AT1 receptor by Ang II accelerates the progression of this disorder, while AT2 receptor activation has a protective effect [126]. Elevated levels of Ang II are associated with depression and hyperactivity of the hypothalamic–adenohypophyseal–testicular (HAT) axis [127, 128]. The injection of exogenous Ang II produces depressive and anxious states, accompanied by increased expression of GABAAR α1 [129]. The use of telmisartan or losartan reduces depressive/anxiety effects as well as pro-inflammatory mediators in various experimental models, indicating AT1 receptor involvement in these models [127, 128, 130, 131]. The modulating effect of the AT2 receptor on the development of depressive behaviors has also been documented [132]. Genetic studies have revealed associations between various polymorphisms of RAS components and depression. Specifically the ACE A2350G genotype and the AT1R A1166C genotype have been linked to depression [133–135]. Collectively, these findings suggest that Ang II is a likely molecule that induces depression. While inflammation plays a beneficial role in restoring homeostasis [136], its chronic persistence can induce chronic inflammation with neuronal damage and decrease in brain neurotropic factors [137–139], events that are crucial in many neurological and psychiatric conditions including depression [137, 140–144]. Consequently, it is proposed that depression results from alterations in immune pathways associated with inflammation [145, 146], characterized by increased levels of pro-inflammatory cytokines and microglia activation [145, 147–150]. Apart from its vasopressor function, Ang II triggers inflammation through the NF-kB transcription factor pathway, leading to the production of various pro-inflammatory cytokines and oxidative stress, among other effects [77–81]. This suggests that the inflammatory effects could be the primary mechanism underlying RAS-induced depression. A growing body of evidence points toward the involvement of Ang II in the pathophysiology of depression, coupled with the fact that anti-RAS drugs reduce oxidative stress, inflammation and depressive behavior [76].

The pathophysiology of depression is linked to biochemical alterations in the central nervous system. In this regard, neuroimaging studies have located biochemical alterations in various areas of the brain, including the orbitofrontal cortex, anterior cingulate cortex, anterior insula, amygdala, hippocampus, basal ganglia, thalamus, and cerebellum [151].

Depression is initially related to the decrease in 5HT. When 5HT is released into the neuronal inter-synaptic space, it acts on the post-synaptic receptors (5HTR) and the pre-synaptic receptors (5HT1AR; autoreceptors). Depletion of 5HTR or overexpression of 5HT1AR is involved in the induction of depression by glutamate (Glu) reduction [152, 153]. This effect leads to the upregulation of two receptors, N-methyl-d-aspartate receptor (NMDAR) and the amino-methyl propionic acid receptor (AMPAR). Their activation reduces the expression of BDNF and induces inhibition of the neural plasticity and depression [152–155] (Fig. 4).

Fig. 4.

Molecular mechanisms of depression. A Serotonin (5HT) is derived from tryptophan (Trp), which upon entering the inter-synaptic space activates the heterologous 5HT receptors (5HTR) located on the postsynaptic neuron surface and the autologous receptors (5HT1AR) located on the pre-synaptic neuron surface. The decrease in 5HT in the inter-synaptic space due to decreased production, increased 5HT1AR receptors, or decreased 5HTR receptors induces depression. B Over-expression of pre-synaptic 5HT1A which inhibits the release of 5HT from presynaptic neurons or down-regulation of 5HTR which mediates an action of 5HT at postsynaptic neurons, leading to the reduction of glutamate (Glu) and upregulation of N-methyl-D-aspartate receptors (NMDAR) and upregulation of amino-methyl propionic acid receptors (AMPAR). These changes reduce expression of brain-derived neurotrophic factor (BDNF) and impairment of neuronal plasticity inducing depression. Additionally, several cytokines are involved in the induction of depression during the neuroinflammation. Interleukin 2 (IL-2), interferon-gamma (INF-Y), and tumor necrosis factor-alpha (TNF-α) activate the enzymes indoleamine 2,3-dioxygenase (IDO) and kynurenine monooxygenase (KMO). The activation of IDO and KMO induced by cytokines produces an increase in quinolinic acid, which is an agonist of NMDAR and induces decreased BDNF expression and depression. Pro-inflammatory cytokines can modify glutamate signaling by increasing glutamate receptors (GLUR) accompanied by glutamate release, which is toxic to the central nervous system and associated with depression

In addition to 5HT deficiency linked to depression, there are different events related to the induction of depression, such as the increased activation of glutamate receptors [156] and the activation of the immune system, expressed by the production of several pro-inflammatory cytokines, among these cytokines are interleukin 2 (IL-2), interferon-gamma (INF-Y), and tumor necrosis factor-alpha (TNF-α) [157]. These cytokines activate the enzyme indoleamine 2,3-dioxygenase (IDO) and the kynurenine monooxygenase (KMO), with the consequent reduction of 5HT and depression [156, 157]. Additionally, the activation of IDO and KMO induced by cytokines produces an increase in quinolinic acid, which is an agonist of NMDAR and induces the reduction of BDNF expression [156, 157]. Excessive production of pro-inflammatory cytokines can modify the glutamate signaling by increasing glutamate receptors and glutamate release, which is toxic to the CNS, and associated with depression [158] (Fig. 4). During brain inflammatory events, IDO activation occurs mainly in microglial cells, metabolizing Trp to quinolinic acid; astrocytes have the enzymes that counteract IDO activity, which have been reported to be decreased in depression [156, 157]. Therefore, the activation of the immune response and the astrocyte/microglia imbalance leads to decreased 5HT expression and increased glutaminergic response [159].

The biochemical mechanisms of depression are linked to cellular alterations. Among the alterations that are linked to depression are oxidative stress, mitochondrial dysfunction and neuroinflammation, which can be regulated by RAS [160]. Different studies have demonstrated the link of Ang II with the pathogenesis of depression [75, 93–97, 99], reporting that blocking AT1 receptor (losartan, valsartan) and its production (captopril, enalapril) can be effective in depression [161, 162]. The involvement of Ang II in emotional disorders like depression has been established, potentially driven by neuroinflammation and oxidative stress [163].

Over-activation of RAS in the brain is linked to Ang II-mediated pro-inflammatory events which can contribute to depression in individuals with diabetes [11, 16, 30, 41]. Moreover, major depression in diabetes involves the activation of systemic pro-inflammatory response, characterized by increased production of various cytokines that can access the brain and interact with all domains related to depression, including neurotransmitter metabolism, neuroendocrine function, and neural plasticity, leading to oxidative stress, neurotoxicity, and loss of glial elements, aligning with the features of depressive disorders [164]. Blockade of AT1 receptors by candesartan decreases depression and AT1R expression in patients with diabetes [21].

Additionally, elevated oxidative stress (superoxide anion) has been correlated with increased number of Ang II-positive cells in cerebrum and cerebellum of rats with experimental depression [19]. Notably, superoxide anion contributes to the amplification of Ang II-mediated signaling in the paraventricular nucleus during diabetes [16]. Brain Ang II expression during neuroinflammation has also been implicated in elevated expression of adhesion molecules (ICAM-1, LFA-1) and CD8-positive cells in cerebrum and cerebellum of depressed rats with diabetes, events that are mitigated by losartan and enalapril treatment [9]. Experimental studies have demonstrated the connection between brain Ang II expression of rats with diabetes and depressive behavior, associated with ultra-structural changes, oxidative stress, and pro-inflammatory processes. Ultrastructural analyses from these rats showed abnormalities in cerebrum, cerebellum and hypothalamus of rats with depression, including degenerative alterations in neurons and glial cells, cellular and mitochondrial swelling, dispersion of pre-synaptic vesicles, neurofilament fragmentation, and disruptions in myelin and oligodendrocytes alterations. These observations imply an association between CNS cellular modifications and depressive behavior in rats with diabetes [165]. In this regard, the brain Ang II effects depend on AT1 receptor stimulation. Excessive brain AT1 receptor activity associates with hypertension and heart failure, brain ischemia, abnormal stress responses, blood–brain barrier breakdown and inflammation leading to neuronal injury, the incidence and progression of neurodegenerative events, mood and traumatic brain disorders, and cognitive decline [77, 96].

Collectively, these findings underscore the role of Ang II as an inductor of pro-inflammatory molecules and oxidative stress in the CNS during experimental diabetes, suggesting its involvement in depressive behavior.

Elevated circulating levels of galectin 3 (Gal3) have been reported in individuals with both types 1 and 2 diabetes [166, 167]. Galectin 3 is associated with insulin resistance, inflammation, and mild cognitive impairment in type 2 diabetes mellitus patients [167]. Importantly, high Gal3 levels are linked to increased risk of Alzheimer's disease, cardiovascular disorders, cancers, and all-cause mortality in individuals with depression and diabetes [168–171]. Furthermore, it has been reported that the effects of Ang II may be partly mediated by Gal3 [171, 172], and that Ang II can increase the expression of Gal 3 [173–175] establishing the relationship Ang II- Gal3- depression. Given the presence of Ang II and Gal3 in the CNS [174–176], it is plausible that they jointly contribute to the induction of depression in patients with diabetes (Fig. 5).

Fig. 5.

Role of galectin 3 in depression induced by angiotensin II during diabetes. The production of angiotensin II (Ang II) in the central nervous system (CNS) and that produced peripherally can determine the interaction of this molecule with its AT1 receptor in the CNS and induce depression in diabetes. High circulating levels of galectin 3 (Gal3) in patients with types 1 and 2 diabetes have been reported. Galectin 3 contributes to insulin resistance, inflammation and mild cognitive impairment in type 2 diabetes mellitus patients. Galectin 3 is involved in depression and obsessive disorders, as well as high circulating levels of this protein are associated with symptoms of depression in humans including patients with type 1 diabetes. It has also been reported that in part the effects of Ang II are mediated by Gal3. In this regard, the presence of Ang II and Gal3 in the CNS could mediate the induction of depression in diabetic patients, suggesting an Ang II-galectin 33 depression pathway during diabetes. ACE 1: angiotensin-converting enzyme 1; ACE 2: angiotensin-converting enzyme 2; Ang I: angiotensin I; CS: circulation system

As above exposed various studies suggested a connection between Ang II blockers and reduced depressive symptoms in diabetes although underlying mechanisms of Ang II-induced depression are unclear. Ang II probably has various mechanisms of inducing depression. The increased activity of Ang II in diabetes can induce pro-inflammatory events that induce the activation of IDO and KMO. These activated enzymes act by decreasing the production of 5HT and increasing the production of quinolinic acid that acts on NMDAR inducing decreased BDNF expression. Both decreased BDNF expression and decreased 5HT production are strongly linked to depression. Additionally, Ang II can induce the production of Gal3 which has effect on the induction of depression. Neuroinflammation induced by Ang II during diabetes can alter brain cells, both morphologically and functionally, which can be associated with functional disorders that lead to depression. Furthermore, Ang II is capable of inducing oxidative stress in diabetes [177, 178], associated with depressive status [163] (Fig. 6). The depressive state in patients with diabetes not only results in a reduced quality of life but also diminishes treatment adherence and metabolic control, leading to elevated morbidity and mortality rates.

Fig. 6.

Mechanisms of angiotensin II in the induction of depression in diabetes. Angiotensin II (Ang II) probably has various mechanisms of inducing depression in diabetes. The increased activity of Ang II in diabetes can induce a pro-inflammatory state that induces the activation of IDO (indoleamine 2,3-dioxygenase) and KMO (kynurenine monooxygenase). These activated enzymes act by decreasing the production of serotonin (5HT) and increasing the production of quinolinic acid which acts on NMDAR inducing decreased BDNF (brain-derived neurotrophic factor) expression. Both decreased BDNF expression and decreased 5HT production are linked to depression. Ang II can also induce the production of galectin 3 which has effect on the induction of depression. Neuroinflammation induced by Ang II during diabetes can alter brain cells, event that can be associated with functional disorders that lead to depression. Furthermore, Ang II is capable of inducing oxidative stress in diabetes associated with depressive status. Trp: tryptophan; 5HT1AR: autologous receptors; 5HTR: 5HT receptor; Glu: glutamate; NMDAR: N-methyl-D-aspartate receptors; AMPAR: amino-methyl propionic acid receptors

Conclusions

Angiotensin II, functioning as a molecule that triggers inflammatory processes both within its CNS locations and through its peripheral production, possesses the capacity to influence the expression of depressive behaviors in diabetes. Considering the common expression of this molecule in diabetes and the frequent occurrence of depression as a manifestation of this disease, it can be inferred that Ang II might serve as the primary instigator of depression in diabetes. Ang II probably exerts its action through mechanisms that involve reduction of 5HT, decrease in BDNF, increase in Gal3, oxidative stress and cellular damage in the CNS. These findings underscore the potential approach of addressing diabetes not only as an endocrine disorder and inflammatory process but also as an avenue to manage the associated depression within this condition by the use of anti-Ang II treatment.

Authors contribution

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Jesús A Mosquera-Sulbaran, Adriana Pedreañez, Renata Vargas, Yenddy Carrero, Juan P Hernandez-Fonseca and Hugo Hernandez-Fonseca The first draft of the manuscript was written by Jesús A Mosquera-Sulbaran and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declarations

Conflict of interest

The author declare that they have no conflict of interest.

Informed consent

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Research involving Human Participants and/or Animals

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