Aldosterone, SGK1, and ion channels in the kidney

Abstract

Hyperaldosteronism, a common cause of hypertension, is strongly connected to Na+, K+, and Mg2+ dysregulation. Owing to its steroidal structure, aldosterone is an active transcriptional modifier when bound to the mineralocorticoid receptor (MR) in cells expressing the enzyme 11β-hydroxysteroid dehydrogenase 2, such as those comprising the aldosterone-sensitive distal nephron (ASDN). One such up-regulated protein, the ubiquitous serum and glucocorticoid regulated kinase 1 (SGK1), has the capacity to modulate the surface expression and function of many classes of renal ion channels, including those that transport Na+ (ENaC), K+ (ROMK/BK), Ca2+ (TRPV4/5/6), Mg2+ (TRPM7/6), and Cl− (ClC-K, CFTR). Here, we discuss the mechanisms by which ASDN expressed channels are up-regulated by SGK1, while highlighting newly discovered pathways connecting aldosterone to nonselective cation channels that are permeable to Mg2+ (TRPM7) or Ca2+ (TRPV4).

Does fludrocortisone treatment cause hypomagnesemia in children with primary adrenal insufficiency?

“…These processes occurred via genomic signalling cascades, related to mineralocorticoid receptors. They also reported that eplerenone, a mineralocorticoid receptor blocker, inhibited the TRPM7 current [4]. On the other hand, Sontia et al [40] showed that aldosterone reduced expression of renal TRPM7 without effecting TRPM6.…”

“…Non-genomic pathways include mineralocorticoid receptor, EGF receptor, and Gprotein coupled receptor-dependent mechanisms as well as mineralocorticoid receptorindependent actions [35][36][37][38][39]. Valinsky et al [4] showed that aldosterone promotes the plasma membrane expression of TRPM7, and therefore TRPM7 flow. These processes occurred via genomic signalling cascades, related to mineralocorticoid receptors.…”

“…Aldosterone is a mineralocorticoid that secreted from adrenal glands and has a regulator effect on blood pressure, water and electrolyte homeostasis. It increases sodium (Na + ) reabsorption in both distal, connecting tubules or collecting ducts of the nephrons [4]. Also, aldosterone is known to increase magnesium excretion by direct and indirect effects on renal tubular cells [5].…”

SPX-101 is stable in and retains function after exposure to cystic fibrosis sputum

“…ENaC can be regulated by a variety of proteases found in CF sputum [43]. Moreover, the expression level of ENaC and SPLUNC1 can be regulated by a number of hormones and soluble proteins [30,44]. Small molecule inhibitors of ENaC such as amiloride and its derivatives work by reducing Po, but the channels remain on the surface of cells.…”

Virtual Screening Approach to Identify High-Affinity Inhibitors of Serum and Glucocorticoid-Regulated Kinase 1 among Bioactive Natural Products: Combined Molecular Docking and Simulation Studies

“…Since SGK1 is regulated by a wide variety of signals, it has many functions and is reported to be involved in the regulation of several carriers and ion channels, including the epithelial sodium channel (EnaC), the renal outer medullary K + channel (ROMK), the voltage-gated K + and Na + channel, the Na + /K + 2Cl − cotransporter (NKCC2), the glutamate transporters, etc. [7,8]. One of the mechanisms whereby SGK1 regulates channels is through the phosphorylation of Nedd4 −2 , a ubiquitin ligase that targets channels for degradation.…”