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negative regulation of angiotensin-activated signaling pathway

Definition

Target type: biologicalprocess

Any process that stops, prevents, or reduces the frequency, rate or extent of the angiotensin-activated signaling pathway. [GOC:lf, PMID:28784619]

Negative regulation of angiotensin-activated signaling pathway involves a complex interplay of molecular mechanisms to control the activity of the renin-angiotensin system (RAS). The RAS is a crucial hormonal system that regulates blood pressure, electrolyte balance, and fluid homeostasis. Dysregulation of the RAS can contribute to cardiovascular disease, kidney disease, and other health problems.

Angiotensin II (Ang II), the main effector of the RAS, exerts its effects by binding to the angiotensin II type 1 receptor (AT1R). This binding triggers a cascade of intracellular signaling events, leading to vasoconstriction, aldosterone production, and other downstream effects.

Negative regulation of Ang II-activated signaling is essential for maintaining homeostasis and preventing excessive activation of the RAS. This regulation occurs at multiple levels:

1. **Reduced Ang II Production:**
- **Renin Inhibition:** Renin, the first enzyme in the RAS, is negatively regulated by various factors, including feedback mechanisms from Ang II itself. Ang II can stimulate the release of vasoactive peptides like bradykinin, which inhibit renin release.
- **Angiotensin-Converting Enzyme (ACE) Inhibition:** ACE inhibitors are drugs that block the conversion of angiotensin I to Ang II, effectively reducing Ang II levels in the body.
- **Angiotensin II Degradation:** Angiotensinases, enzymes that break down Ang II, are also involved in negative regulation.

2. **AT1R Downregulation and Desensitization:**
- **Internalization and Degradation:** AT1R can be internalized and degraded after prolonged exposure to Ang II.
- **Desensitization:** The receptor can undergo desensitization, becoming less responsive to Ang II binding. This can involve phosphorylation of the receptor by kinases, leading to a conformational change that reduces its affinity for Ang II.
- **Alternative Signaling Pathways:** Activation of alternative signaling pathways, such as the angiotensin II type 2 receptor (AT2R), can counteract the effects of AT1R signaling.

3. **Counteracting Mechanisms:**
- **Vasodilation:** Vasodilators like nitric oxide (NO) and prostaglandins can oppose the vasoconstrictive effects of Ang II.
- **Sodium Excretion:** Increased sodium excretion, mediated by mechanisms like atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), counteracts the sodium retention induced by Ang II.

4. **Feedback Mechanisms:**
- **Ang II-induced Release of Vasoactive Peptides:** Ang II itself can trigger the release of vasoactive peptides like bradykinin, which inhibit renin release and counteract Ang II's effects.
- **Feedback Inhibition of the RAS:** Ang II, when present in high levels, can directly inhibit the activity of the RAS by suppressing renin release and Ang II synthesis.

Overall, negative regulation of the Ang II-activated signaling pathway involves a complex network of mechanisms that work in concert to maintain a delicate balance in the RAS. Disruption of these regulatory processes can contribute to various pathological conditions.'
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Proteins (1)

ProteinDefinitionTaxonomy
Serine/threonine-protein phosphatase 2B catalytic subunit alpha isoformA protein phosphatase 3 catalytic subunit alpha that is encoded in the genome of human. [PRO:CNA, UniProtKB:Q08209]Homo sapiens (human)

Compounds (3)

CompoundDefinitionClassesRoles
tacrolimustacrolimus (anhydrous) : A macrolide lactam containing a 23-membered lactone ring, originally isolated from the fermentation broth of a Japanese soil sample that contained the bacteria Streptomyces tsukubaensis.

Tacrolimus: A macrolide isolated from the culture broth of a strain of Streptomyces tsukubaensis that has strong immunosuppressive activity in vivo and prevents the activation of T-lymphocytes in response to antigenic or mitogenic stimulation in vitro.
macrolide lactambacterial metabolite;
immunosuppressive agent
tamoxifenstilbenoid;
tertiary amino compound
angiogenesis inhibitor;
antineoplastic agent;
bone density conservation agent;
EC 1.2.3.1 (aldehyde oxidase) inhibitor;
EC 2.7.11.13 (protein kinase C) inhibitor;
estrogen antagonist;
estrogen receptor antagonist;
estrogen receptor modulator
cyclosporineramihyphin A: one of the metabolites produced by Fusarium sp. S-435; RN given refers to cpd with unknown MFhomodetic cyclic peptideanti-asthmatic drug;
anticoronaviral agent;
antifungal agent;
antirheumatic drug;
carcinogenic agent;
dermatologic drug;
EC 3.1.3.16 (phosphoprotein phosphatase) inhibitor;
geroprotector;
immunosuppressive agent;
metabolite