Aldosterone-Regulated Sodium Transport and Blood Pressure

Abstract

Aldosterone is a major mineralocorticoid steroid hormone secreted by glomerulosa cells in the adrenal cortex. It regulates a variety of physiological responses including those to oxidative stress, inflammation, fluid disruption, and abnormal blood pressure through its actions on various tissues including the kidney, heart, and the central nervous system. Aldosterone synthesis is primarily regulated by angiotensin II, K⁺ concentration, and adrenocorticotrophic hormone. Elevated serum aldosterone levels increase blood pressure largely by increasing Na⁺ re-absorption in the kidney through regulating transcription and activity of the epithelial sodium channel (ENaC). This review focuses on the signaling pathways involved in aldosterone synthesis and its effects on Na⁺ reabsorption through ENaC.

Keywords: ACTH; CYP11B2; Dot1; ENaC; SGK1; aldosterone; angiotensin II; potassium.

Figure 1

Hypotension-induced activation of the renin-angiotensin-aldosterone system. As blood pressure drops, juxtaglomerular cells receive signals from macula densa cells and the sympathetic nervous system and secrete renin into the circulation. Renin hydrolyzes liver-synthesized angiotensinogen into inactive ANG I. ANG I is converted to active ANG II by ACE. ANG II stimulates glomerulosa cells in the adrenal cortex to secrete aldosterone and the anterior pituitary gland in the brain to secrete the ACTH, which also results in aldosterone production. High K⁺ concentration stimulates aldosterone secretion from glomerulosa cells. Aldosterone increases Na⁺ reabsorption, K⁺ and H⁺ secretion in ASDN leading to an increase in blood pressure. ANG I, angiotensin I; ANG II, angiotensin II; ACE, angiotensin-converting enzyme; ASDN, aldosterone-sensitive distal nephron.

Figure 2

Aldosterone biosynthesis pathway. Cholesterol is transported to the inner mitochondrial membrane, where it is hydroxylated and cleaved by cytochrome P450scc to produce pregnenolone. Pregnenolone is relocated to the membrane of smooth endoplasmic reticulum, where it is oxidized by HSB3D to produce progesterone. Eleven deoxycorticosterone is generated by CYP21-mediated hydroxylation of progesterone and moves back to the inner mitochondrial membrane, where it is subject to ADS-catalyzed sequential 11-hydroxylation, 18-hydroxylation, and 18-oxidation, producing corticosterone, 18-OH corticosterone, and finally aldosterone, respectively. P450scc, cytochrome P450 side chain cleavage enzyme; HSD3B, 3β-hydroxysteroid dehydrogenase; CYP 21, 21 hydroxylase; ADS, aldosterone synthase.

Figure 3

Cellular mechanisms leading to increased aldosterone production upon angiotensin II, ACTH, and K⁺ stimulation. Ang II binds to AT1R, leading to dissociation of the alpha subunit and activation of PLC. PLC hydrolyses PIP2 into DAG and IP3. IP3 binds to its receptor on the SER leading to the release of Ca²⁺ stores. Ca²⁺ activates CaMK, which causes an increase in ADS expression through CREB. DAG activates PKC to phosphorylate Src, which phosphorylates EGFR leading to activation of p42/p44 mitogen-activating protein kinase pathway. P42/p44 phosphorylates CEH to hydrolyze cholesterol esters located in the lipid droplets, making them available for transport to the inner mitochondrial membrane by STAR. PKC also phosphorylates and activates STAR. Cholesterol is used for aldosterone synthesis. ACTH binds its ACTHR leading to the activation of adenylate cyclase, which produces cAMP from ATP. cAMP triggers PKA-mediated phosphorylation and activation of STAR. PKA also phosphorylates L and T type Ca²⁺ channels causing Ca²⁺ influx. PKA increases the expression of ADS through relieving SF1-mediated inhibition of STAR. High extracellular K⁺ concentration depolarizes cells and leads to activation of L and T type Ca²⁺ channels, which allow calcium inflow from the extracellular space. ANG II, angiotensin II; AT1R, angiotensin II receptor type 1; GPCR, G protein-coupled receptor; PLC, phospholipase C; PIP2, phosphatidylinositol 4,5-bisphosphate; DAG, diacylglycerol; IP3, inositol 1,4,5 triphosphate; SER, smooth endoplasmic reticulum; CaMK, Ca²⁺/calmodulin-dependent protein kinase; ADS, aldosterone synthase; CREB, cAMP-response element binding protein; PKC, protein kinase C; EGFR, epidermal growth factor receptor; CEH, cholesterol ester hydrolase; STAR, steroid acute regulatory protein; ACTH, adrenocorticotropic hormone; ACTHR, adrenocorticotropic hormone receptor; SF1, steroidogenic factor 1.

Figure 4

Aldosterone regulates epithelial sodium channel (ENaC) activity and degradation. Aldosterone-bound MR translocates to the nucleus and induces transcription of USP 2-45, SGK1, and GILZ. SGK1 phosphorylates WNK4 and dampens its inhibitory action on ENaC activity. Nedd4-2 ubiquitinates ENaC and signals it for proteasomal degradation. Wnk4 is targeted to proteasomal degradation by KLHL3-Cul3 ubiquitin ligase. SGK1 inhibits this process by phosphorylating Nedd4-2 reducing its affinity to ENaC. USP2-45 removes UB from ENaC preventing its degradation. SGK1 requires phosphorylation events in order to achieve full activity, which is accomplished by PDK1, Wnk1, and mTORC. In the absence of aldosterone, SGK1 is subject to ERAD. However, in the presence of aldosterone GILZ inhibits this process increasing the stability of SGK1. MR, mineralocorticoid receptor; SGK1, serum glucocorticoid-induced kinase 1; GILZ, glucocorticoid-induced leucine zipper 1; Nedd4-2, Neural precursor cell expressed developmentally downregulated gene 4; ENaC, epithelial sodium channel; UB, ubiquitin; PDK1, pyruvate dehydrogenase kinase; ERAD, endoplasmic reticulum-associated degradation.

Figure 5

Epigenetic control of αENaC transcription. Under basal conditions (A), Af9 recruits Dot1a to form a nuclear complex, which indirectly or directly through Af9 DNA-binding activity binds specific sites of the αENaC promoter, leading to hypermethylation of histone H3 K79 and repression of αENaC transcription. Af17 relieves the repression by competing with Af9 for binding Dot1a and promoting Dot1a redistribution from the nucleus to cytoplasm. In the presence of aldosterone (B), αENaC transcription is induced by a variety of mechanisms. Through the classical action, aldosterone binds and activates the mineralocorticoid receptor to bind the glucocorticoid response element in the αENaC promoter and transactivate αENaC. In parallel, aldosterone releases Dot1a–Af9-mediated repression by reducing the formation of the complex through three mechanisms: downregulating Dot1a and Af9 expression presumably via nuclear receptor-dependent or -independent (not shown) mechanisms, decreasing the Dot1a–Af9 interaction via SGK1-mediated phosphorylation of Af9 at Ser435, and counterbalancing Dot1a–Af9 complex by activating MR to compete for binding Af9. These actions collectively result in histone H3 K79 hypomethylation at specific subregions of the αENaC promoter. In all cases, Af9-free Dot1a binds DNA nonspecifically and catalyzes histone H3 K79 methylation throughout the genome under basal conditions (not shown). Revised from Chen et al. (2015). Dot1a: disruptor of telomeric silencing 1a. Meth: methylation. αENaC: α epithelial sodium channel. NR: nuclear hormone receptor. SGK1: serum glucocorticoid-induced kinase 1.