Exploring the Evidence Implicating the Renin-Angiotensin System (RAS) in the Physiopathology of Mood Disorders

Mood disorders include Major Depressive Disorder (MDD), Bipolar Disorder (BD) and variations of both. Mood disorders has a public health significance with high comorbidity, suicidal mortality and economic burden on the health system. Research related to mood disorders has evolved over the years to relate it with systemic conditions. The Renin Angiotensin System (RAS) has been noticed to play major physiological roles beyond renal and cardiovascular systems. Recent studies have linked RAS not only with neuro-immunological processes, but also with psychiatric conditions like mood and anxiety disorders. In this comprehensive review, we integrated basic and clinical studies showing the associations between RAS and mood disorders. Animal studies on mood disorders models - either depression or mania - were focused on the reversal of behavioral and/or cognitive symptoms through the inhibition of RAS components like the Angiotensin- Converting Enzyme (ACE), Angiotensin II Type 1 receptor (AT1) or Mas receptors. ACE polymorphisms, namely insertion-deletion (I/D), were linked to mood disorders and suicidal behavior. Hypertension was associated with neurocognitive deficits in mood disorders, which reversed with RAS inhibition. Low levels of RAS components (renin activity or aldosterone) and mood symptoms improvement with ACE inhibitors or AT1 blockers were also observed in mood disorders. Overall, this review reiterates the strong and under-researched connection between RAS and mood disorders.

Influence of AT1 blockers on obesity and stress-induced eating of cafeteria diet

Based on findings that treatment with AT1 receptor blocker (ARB) prevents diet-induced obesity and that the activity of the hypothalamic–pituitary–adrenal (HPA) axis is stimulated by AngII and blocked by ARBs, we aimed to investigate whether ARB treatment can reduce stress-induced eating of cafeteria diet (CD), thus contributing to alterations in eating behavior. Sprague–Dawley rats were fed with chow or CD and treated with telmisartan (TEL, 8 mg/kg/day) or vehicle. At weeks 2 and 12, rats were stressed over five consecutive days by restraint stress (RS, 4 h) and by additional shaking at d5. Tail blood was sampled during RS to determine hormone levels. During the first period of RS, ACTH and corticosterone responses were diminished at d5 in CD- compared to chow-fed rats. Independently of feeding, TEL did not reduce stress hormones. Compared to food behavior before RS, the stress-induced CD eating increased in controls but remained unchanged in TEL-treated rats. After 12 weeks, TEL reduced weight gain and energy intake, particularly in CD-fed rats. Similar to the first RS period, corticosterone response was reduced in CD-fed rats at d5 during the second RS period. TEL did not further reduce stress hormones and did not lessen the CD eating upon RS. We conclude that CD feeding compensates for stress reactions. However, stress-induced CD eating was only reduced by TEL after short term, but not after long-term drug treatment. Thus, the potency of ARBs to lower HPA activity only plays a minor role in reducing energy intake to prevent obesity.

Improved Insulin Sensitivity after Long-Term Treatment with AT1 Blockers Is Not Associated with PPARγ Target Gene Regulation

In both cell culture experiments and in vivo studies, a number of angiotensin II type 1 (AT1) receptor antagonists activated the peroxisome proliferator-activated receptor-γ (PPARγ). This mechanism has been discussed to be, at least in part, responsible for the improvement in glucose metabolism observed in animal studies and clinical trials. To investigate whether the PPARγ-dependent mechanism may represent a valid target for chronic therapy, spontaneously hypertensive rats (SHR) were fed either with a cafeteria diet (CD) or standard chow. CD-fed SHR were simultaneously treated with either telmisartan (TEL; 8 mg/kgbody weight·d) or candesartan (CAND; 10 mg/kgbody weight·d) for 3 months because TEL, but not CAND, has been demonstrated to be a strong activator of PPARγ. After 3 months, chow- and CD-fed controls were hypertensive, whereas TEL and CAND treatment resulted in normalized blood pressures in SHR. Body weight and the amount of abdominal fat (determined by magnetic resonance imaging) were higher in CD- than in chow-fed SHR. After TEL or CAND, body weight, abdominal fat quantity, and adipocyte size returned to normal. In glucose tolerance tests, the glucose responses were comparable in the TEL- and CAND-treated SHR and obese controls, whereas the insulin response was almost halved by AT1 blockade. Expression of PPARγ target genes aP2, FAT CD36, FASn, and PEPCK remained unaltered at the protein level in visceral fat after TEL and CAND compared with the CD-fed controls. Because the expression of examined PPARγ target genes was not affected, we concluded that improved insulin sensitivity after long-term treatment with AT1 blockers was not related to a PPARγ-dependent mechanism.