Aldosterone, SGK1, and ion channels in the kidney.

William C Valinsky,Alvin Shrier,Rhian M Touyz

doi:10.1042/cs20171525

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).

Highlights

In 2017, hypertensive blood pressure thresholds were lowered such that stage 1 hypertension commences at 130 mmHg and/or 80 mmHg [1]; down from 140 mmHg/90 mmHg [2]
serum and glucocorticoid regulated kinase 1 (SGK1) phosphorylated ROMK1 at Ser44, and this was correlated with increased plasma membrane abundance of ROMK1 [46], an effect further dependent on the trafficking/transport protein Na+/H+ exchange regulatory factor 2 (NHERF2) [47]. These findings indicate that SGK1 increases ROMK1 c 2018 The Author(s)
Pertaining to aldosterone, we demonstrated that mice injected with aldosterone have a lower membrane to cytosol fraction of renal TRPM6 compared with control animals, an effect that was rescued when mice were fed high Mg2+ diets [101]

Summary

Introduction

In 2017, hypertensive blood pressure thresholds were lowered such that stage 1 hypertension commences at 130 mmHg (systolic) and/or 80 mmHg (diastolic) [1]; down from 140 mmHg/90 mmHg [2]. Prior to these changes, global data showed hypertensive rates of 22–30% in the total population [2,3,4,5,6], with the more stringent definitions, these rates will no doubt climb. It is critically important that the ion regulatory pathways of aldosterone are fully understood to understand the unintended consequences of aldosterone-related treatments

Objectives

Findings

Conclusion