Clinical Science (2018) 132 173–183 https://doi.org/10.1042/CS20171525
Review Article Aldosterone, SGK1, and ion channels in the kidney
William C. Valinsky1, Rhian M. Touyz2 and Alvin Shrier1 1Department of Physiology, McGill University, 3649 Promenade Sir William Osler, Montreal, Quebec H3G 0B1, Canada; 2Institute of Cardiovascular and Medical Sciences, University of Glasgow, BHF GCRC, 126 University Place, Glasgow G12 8TA, U.K. Correspondence: Alvin Shrier ([email protected]) Downloaded from http://portlandpress.com/clinsci/article-pdf/132/2/173/829006/cs-2017-1525.pdf by guest on 14 October 2020 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 ex- pressing the enzyme 11β-hydroxysteroid dehydrogenase 2, such as those comprising the aldosterone-sensitive distal nephron (ASDN). One such up-regulated protein, the ubiqui- tous 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 al- dosterone to nonselective cation channels that are permeable to Mg2+ (TRPM7) or Ca2+ (TRPV4).
Introduction In2017,hypertensiveblood pressure thresholdswerelowered such that stage 1 hypertension commences at 130 mmHg(systolic) and/or 80 mmHg(diastolic) [1]; down from 140 mmHg/90 mmHg[2].Priorto these changes, globaldata showed hypertensive rates of 22–30% in the total population [2-6],however with the more stringent definitions, these rates will no doubt climb. Moreover, the prevalence of hyper- tension is expected to further increase over time due to increasing rates of obesity and aprogressively aging demographic [3]. Clinically, hyperaldosteronism is often observed in resistant hypertension [4] and is a common cause of secondary hypertension [5-8].Thisisofmajor significance because hyperaldosteronism is associ- ated with a plethora of cardiovascular comorbidities and is hallmarked by electrolyte dysregulation [9]. Moreover, drugs that target aldosterone and its mineralocorticoid receptor, such as spironolactone and eplerenone, are increasinglybeingused in the management of various pathologies, including hyperten- sion, heart failure, arrhythmias and renaldisease [10,11]. Therefore, it is critically important that the ion regulatory pathways of aldosterone are fullyunderstood to understand the unintended consequences of aldosterone-related treatments. Ion transport abnormalities in hyperaldosteronism are to be expected,astheearliest research into al- dosterone showed that the steroid hormone decreases the excretion of Na+ [12] and increases the ex- cretion of K+ andH+ [13]. Mechanistically, most effects of aldosterone are exerted through the min- eralocorticoid receptor (MR), to which aldosterone binds[14]. However, the MRhasequal affinity for aldosterone and glucocorticoids[15], a surprising observation since glucocorticoid plasma concentra- tions are 100–1000 times higher than aldosterone concentrations [16]. To maintain aldosterone sensitiv- Received: 14 November 2017 ity, aldosterone-sensitive cells express 11β-hydroxysteroiddehydrogenase 2 [17], which converts cortisol Revised: 15 December 2017 to cortisone [18],preventingcortisol from interacting with the MR[17]. Within the kidney, immunohis- Accepted: 19 December 2017 tochemical and immunocytochemical experiments have shown that 11β-hydroxysteroiddehydrogenase Version of Record published: localizes to three consecutive segments: the distal convoluted tubule(DCT), connecting tubule(CNT), 19 January 2018 and cortical collecting duct (CCD)[19,20]. Insomespecies,wheretheDCThasbeensubdivided into the