PMID: 21839803

NodeType: Pathway

PMID: 21311022

Notes: Headnote: Arterial hypertension is a chronic increase in blood pressure, which may lead to a variety of cardiovascular diseases, stroke, congestive heart failure, peripheral vascular disease, and renal disease. Hypertension risk factors include obesity, alcohol, smoking, kidney or endocrine diseases, diabetes mellitus, and family history. Aldosterone is a key mineralocorticoid hormone that has a fundamental role in salt and water homeostasis and blood pressure regulation. Signaling description: Aldosterone production is regulated through the continuing action of the local and systemic angiotensin II, circulating adrenocorticotropic hormone (ACTH), and serum potassium levels. The continuous stimuli increase aldosterone secretion by increasing the gene expression of CYP11B2. AngII binds AGTR1 to activate PLC, which causes the hydrolysis of PIP2 to diacylglycerol and IP3, which then binds ITPR1 in the endoplasmic reticulum (ER), releasing calcium (Ca2+) and, thus raising the cytosolic Ca2+ concentrations. Diacylglycerol activates PKC, which phosphorylates PRKD1, which then directly phosphorylates and activates CREB1. Further, CREB1 binds NR4A2, FOS, and STAR transcription factors. Further, FOS inhibits the transcription of CYP17A1 and blocks 17-hydroxypregnenolone synthesis. STAR is a crucial protein for the transport of cholesterol to mitochondria, where biosynthesis of steroids is initiated. NR4A2 plays a major role in the stimulation of CYP11B2 gene expression. Aldosterone is synthesized by CYP11B2. K+ can induce CYP11B2 expression in the adrenal as well as the synthesis of aldosterone. Outcome effects: Modest increases in extracellular K+ depolarize the glomerulosa cell, which activates voltage-dependent, L-type calcium channels such as CACNA1C, CACNA2D1, and CACNB2, and increases Ca2+ influx. The membrane depolarization induced by elevated intracellular K+ concentration (via KCNJ5/ KCNK3) causes the activation of FOS and CREB1 genes. The increased intracellular Ca2+ concentration activates CAMK via calmodulin. CAMK phosphorylates and activates CREB1. Possible activating mutations in KCNJ5 and CYP11B2 enhance their functioning. AngII and increased Ca2+ and K+ influx promote constant aldosterone secretion, which activates the expression of CYP11B2. The overproduction of aldosterone causes aldosteronism and leads to arterial hypertension. Highlighted proteins: Entities with increased level or activity are highlighted in red. Mutated proteins: Mutated genes are shown in white-out style.

Pathway_Author: M. Zharkova  ORCID:0000-0001-8706-9411

Source: Diseases

PMID: 23378101

Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-871d859d-49cd-4737-8bb3-dad3d21e1950