Secondary Logo

Journal Logo

Aldosterone's mechanism of action: roles of lysine-specific demethylase 1, caveolin and striatin

Baudrand, Rene; Pojoga, Luminita H.; Romero, Jose R.; Williams, Gordon H.

Current Opinion in Nephrology and Hypertension: January 2014 - Volume 23 - Issue 1 - p 32–37
doi: 10.1097/01.mnh.0000436543.48391.e0
CIRCULATION AND HEMODYNAMICS: Edited by Matthew R. Weir and Roland C. Blantz

Purpose of review Aldosterone's functions and mechanisms of action are different depending on the tissue and the environmental condition. The mineralocorticoid receptor is present in tissues beyond epithelial cells, including the heart and vessels. Furthermore, aldosterone has direct adverse effects by both genomic and rapid/nongenomic actions not only through a nuclear receptor but also through caveolae-mediated intracellular events. Also, multiple environmental–genetic interactions play an important role in salt-sensitive hypertension (SSH) and aldosterone modulation. These findings have reshaped our vision of aldosterone's role in cardiovascular pathophysiology. This review describes new mediators of aldosterone's mechanisms of action: lysine-specific demethylase 1 (LSD1), caveolin 1 (cav-1) and striatin.

Recent findings LSD1, an epigenetic regulator, is involved in the pathogenesis of SSH in both humans and rodents. In addition, cav-1, the main component of caveolae, plays a substantial role in mediating aldosterone pathways of SSH. The mineralocorticoid receptor interacts with cav-1 and is modulated by sodium intake. Finally, striatin, a scaffolding protein, mediates a novel interaction between signalling molecules and mineralocorticoid receptor's rapid effects in the cardiovascular system.

Summary Substantial progress in aldosterone's functions and mechanisms of action should facilitate the study of cardiovascular diseases and the role of sodium intake in aldosterone-induced damage.

aDivision of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School. Boston, Massachusetts, USA

bDepartment of Endocrinology, School of Medicine, Pontificia Universidad Catolica De Chile, Santiago, Chile

Correspondence to Gordon H. Williams, MD, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital/Harvard Medical School, 221 Longwood Ave, Boston, MA 02115, USA. Tel: +1 617 525 7490; e-mail:

Back to Top | Article Outline


When first identified by Simpson and Tate in 1953, aldosterone was described as a hormone that controlled salt, volume and potassium homeostasis. In fact, several investigators working in the field at this time first gave the name ‘electrocortin’ to this compound because their research focused solely upon its role in electrolyte homeostasis. Perhaps this uni-dimensional view was a reflection of the setting in which aldosterone was first discovered. This initial research used an epithelial cell system, essentially renal tissue. Thus, this approach effectively focused research on aldosterone's role in sodium/potassium homeostasis. Over the next 40 years, investigators documented that aldosterone's primary epithelial mechanism was via a cytosolic receptor with transport to the nucleus. The molecular events induced by aldosterone leading to changes in sodium and potassium handling by the kidney were also identified. Substantial progress was made in identifying the factors that regulate aldosterone secretion and how these factors modify the biosynthetic machinery within the adrenal cortex.

In the last 10 years, it has become clear that this popular view only reflects the tip of the iceberg of aldosterone's functions and mechanisms of action. Aldosterone has more actions than controlling sodium and potassium homeostasis. The mineralocorticoid receptor has been identified in a wide variety of tissues beyond epithelial cells, including endothelial cells, vascular smooth muscle, fibroblasts, adipocytes and myocytes. The function of aldosterone in these cells is very different than the effect aldosterone has on epithelial cells. Furthermore, data support the concept that aldosterone works not only through a nuclear receptor but also through a cell-surface receptor, and intriguingly uses a common membrane mechanism – caveolae – to mediate its intracellular events. These findings have fundamentally reshaped our vision of the actions of aldosterone and its role in cardiovascular physiology and pathophysiology. Herein, we will review the role of three recently identified mediators of aldosterone's mechanism of action: lysine-specific demethylase 1 (LSD1), caveolin and striatin. Articles published in the last 18 months related to these three molecules and aldosterone and the interacting effect of salt intake will be reviewed.

Box 1

Box 1

Back to Top | Article Outline


Hypertension is a highly multigenic heritable trait (up to 40%); however, the currently identified genetic variants account for only a small fraction of the phenotypical differences and disease risk [1▪]. In the recent years, growing evidence has focused on the role of epigenetics, defined as phenotypic variations throughout life by mechanisms that alter gene expression independent of changes in DNA sequence [2]. These epigenetic changes lead to a dynamic modulation of gene expression by several molecular processes including DNA methylation and histone modification [3]. To date, determining the multiple environmental–genetic interactions that trigger these epigenetic changes and whether they are cause or consequence of hypertension remain to be elucidated.

A well studied epigenetic modification is DNA methylation that occurs mainly in cytosine-phosphate-guanine (CpG) dinucleotides, is maintained during cell division in mammals and generally downregulates gene transcription [3]. Recently, Zhang et al.[4▪▪] evaluated the association of ADD1 gene promoter DNA methylation and hypertension. This gene encodes α-adducin, which regulates surface expression of multiple transporters, such as Na+/K+-ATPase, and is a well studied candidate gene for essential hypertension, despite recent meta-analyses with discrepant results [5–7]. This study showed a sexual dimorphism in DNA methylation patterns as risk factors for essential hypertension, with lower CpG1 in women and lower CpG2–5 in men. Classical risk factors for hypertension such as high-sodium diet, obesity and physical inactivity have been linked to changes in DNA methylation levels in other candidate genes, supporting a crucial interaction between environmental factors and changes in gene expression [8–10].

As hypertension is a heterogeneous disease in which several pathogenic mechanisms interplay to increase blood pressure (BP), we and others have used an intermediate phenotype approach for genetic studies [5]. One of the best studied phenotypic traits is salt-sensitive hypertension (SSH), defined as an increase in BP in response to salt loading, with an estimated prevalence of 50–60% within hypertensive individuals [11]. Several mechanisms have been proposed for SSH, including impaired renal sodium handling, reduced renin suppression and dysregulated rennin–angiotensin system in the vasculature, which could be mediated by epigenetic changes in response to high-salt diet [11,12].

As described with DNA, histones can undergo epigenetic modifications such as methylation or acetylation, changing the chromatin structure that packs the DNA, thereby playing an important role in gene regulation. By contrast to DNA methylation, the relaxation of condensed histones is a key step for activating gene expression [13]. Pojoga et al. [14] and Williams et al. [15▪▪] recently described that LSD1 is involved in the pathogenesis of SSH in both animals and humans. LSD1 is a flavin-dependent amine oxidase that can act either as a transcription corepressor, if demethylation occurs at the lysine 4 of histone H3 (H3K4) site, or as a transcription coactivator if demethylation is switched towards the H3K9 site [16]. In a translational approach, Williams et al. [15▪▪] showed that LSD1 heterozygote knockout mice (LSD1+/−) and African-American individuals with polymorphic variants of LSD1 had a similar phenotype that included SSH and decreased aldosterone levels on a high-salt diet. These results support a role of LSD1 as an epigenetic mediator of sodium's effects on BP and renal sodium excretion, although the underlying molecular pathway warrants further investigation (Fig. 1). In addition, the study showed that LSD1 protein levels in kidney and heart tissue were modified by salt intake in wild-type mice, providing new evidence that dietary salt can also modify the expression of a gene known to be an epigenetic regulator per se[15▪▪]. Further, Krug et al.[17▪] showed that LSD1 modulates the interaction of ageing and salt intake on BP. The study included data on LSD1+/− mice that showed a more pronounced age-associated increase in SBP when compared with wild-type after a 1-week high-salt diet. In addition, normotensive white individuals with LSD1 polymorphism rs7548692 showed a significant age–genotype interaction. The observed BP response to dietary salt intake strongly suggested that LSD1 polymorphism not only increased the prevalence of SSH but also modified the ageing effect on salt sensitivity [17▪]. As age and dietary salt intake are well described predictors of hypertension, this study supports the role of LSD1 as an epigenetic regulator that could explain, at least in part, how environmental stressors and physiological processes interact to modify gene expression and the resultant phenotype. Also, this study explored a potential mechanism in the interaction between salt intake and LSD1, showing that LSD1+/- mice had increased total plasma volume in association with increased BP, suggesting that LSD1 is involved in the regulation of whole body sodium homeostasis. Consistent with these results, Mu et al.[18] added new epigenetic information in SSH by reporting that WNK lysine-deficient protein kinase 4 (WNK4) transcription could be downregulated by histone modification. The proposed mechanism is that sodium intake stimulates β2-adrenergic receptor resulting in cyclic AMP inhibition and histone acetylation. Thus, this study suggests that salt loading could also trigger another epigenetic modification resulting in decreased renal WNK4 expression and subsequent sodium retention and hypertension [18].



Back to Top | Article Outline


Caveolae, small invaginations in the cellular membrane, are not only a structural platform for receptors, channels and enzymes but also act as functional modulators of a wide selection of cellular pathways. In cardiovascular and renal tissues, caveolae are particularly abundant and mediate a number of critical signal transduction mechanisms. The main component of plasma membrane caveolae, caveolin 1 (cav-1), has recently drawn growing attention owing to its effects on cellular physiology, from receptor and ion channel activation to signal transduction and intracellular trafficking.

Owing to its role in water and sodium homeostasis, aldosterone is a prime candidate to explain phenotypic abnormalities associated with SSH. Apart from the classical, genomic effects of aldosterone via transcriptional effects of the mineralocorticoid receptor in the nucleus, new evidence suggests that aldosterone can have rapid, nongenomic effects in cardiovascular and renal tissues. Such effects have been characterized to occur via mineralocorticoid receptor activation at the plasma membrane, or via interaction with other receptor pathways typically initiated in caveolae, including the angiotensin II type 1 receptor (AT1R), the epidermal growth factor receptor (EGFR) or the novel G protein coupled receptor GPR30 [19]. Interestingly, Ricchiuti et al. [20] and Gildea et al. [21] have shown that during sodium loading, cav-1 and mineralocorticoid receptor levels are increased in both polar and nonpolar aldosterone target cells (such as cardiac and renal tissues), whereas mineralocorticoid receptor expression is decreased in cardiac and vascular tissues from cav-1 knockout mice [22], consistent with impaired mineralocorticoid receptor signalling in the absence of cav-1. In addition, Pojoga et al. [23] have shown that the mineralocorticoid receptor (like other steroid receptors) colocalizes and coimmunoprecipitates with cav-1 in these tissues and that mineralocorticoid receptor–caveolin complexes are more abundant during sodium loading [20]. These data are consistent with an interplay between cav-1 and mineralocorticoid receptor in modulating mechanisms of salt sensitivity in aldosterone target tissues (Fig. 1). Indeed, Pojoga et al. [22,24] demonstrated that cav-1 deficient mice display profound vascular dysfunction that can be ameliorated by dietary sodium restriction or mineralocorticoid receptor blockade.

Importantly, other pathways modulated by cav-1 have also been implicated in mechanisms of aldosterone signalling and/or salt sensitivity, such as enzymes involved in oxidative stress responses, G-protein coupled receptors, as well as ion channels and transporters. Thus, it was recently shown that mineralocorticoid receptor blockade rescues the cardiovascular phenotype in Dahl salt-sensitive rats via improvements in oxidative stress mediated by the endothelial nitric oxide synthase (eNOS) and NADPH oxidase [25]. These enzymes are not only known regulators of the redox potential inside cells (via their interaction with cav-1) but also key players in the cause of cardiovascular [26] and renal [27] diseases. Furthermore, recent evidence suggests that dietary sodium activates the small GTPase Rac1 in Dahl rat kidney tissues, leading to aldosterone-independent mineralocorticoid receptor activation, oxidative stress and target organ damage [28,29]. Importantly, cav-1 has been shown to be a key player in polyubiquitylation events that control Rac1 intracellular levels and activity [30].

Salt sensitivity is also often associated with abnormal ion transport in cardiovascular and renal tissues. There is now abundant evidence that cav-1 targets to caveolae and modulates aldosterone-sensitive molecules such as the epithelial sodium channel (ENaC) [31], the Na+/K+-ATPase [21,32,33], the Na+/H+ exchanger NHE-1 [34], the Na+/K+/2Cl cotransporter (NKCC2) [35▪] or the large conductance Ca2+ and voltage-activated K+ channels (BKCa) [36]. Initially demonstrated in kidney cells, these effects of cav-1 on aldosterone/mineralocorticoid receptor signalling have been recently extended to nonrenal tissues. Although many of these influences are exerted via changes in cav-1 mediated endocytosis, it has become clear that cav-1 can also facilitate direct signalling at the membrane. Interestingly, a recent study [33] suggests that the alpha-subunit of the Na+/K+-ATPase acts as a cell surface receptor for the nongenomic action of steroids, in a cav-1 dependent manner. Although the study was focused on the effects of progesterone in cultured oocytes, it can be speculated that similar interactions hold true for aldosterone in cardiovascular and renal tissues in vivo. Furthermore, cav-1 plays a critical role in maintaining appropriate urinary sodium excretion and BP homeostasis under conditions of sodium loading [21]. Taken together, these data suggest that caveolae and cav-1 act as modulators of salt sensitivity via an interplay with mineralocorticoid receptor activation in aldosterone target tissues.

Back to Top | Article Outline


Striatin, a scaffolding protein that is abundant in neurons, interacts with mediators of vesicular trafficking and cav-1 and is localized to caveolae. There is growing evidence that striatin facilitates the formation and cross-talk of a membrane signalling complex. Striatin contains a caveolin-binding motif, a coiled-coil structure, a Ca2+-calmodulin-binding site and a large WD-repeat domain [37]. This WD-repeat domain interacts with GPCR-Gαi protein and protein phosphatase 2A, allowing for rapid activation of several transduction molecules including eNOS and mitogen-activated protein kinase.

Striatin has been shown to be a key intermediary of the effects of oestrogen receptor-α (ERα) activation and critical for the rapid/nongenomic effects of oestrogen on Akt and eNOS activation in endothelial cells [38]. In fact, Lu et al. [38] have shown that blockade of the ERα–striatin complex has no effect on ERα-mediated gene transcription in human endothelial cells. Striatin's N-terminal segment interacts with the DNA-binding domain of ERα in endothelial cells that organizes ERα–eNOS membrane signalling leading to rapid nongenomic activation of eNOS. Of interest, overexpression of striatin leads to increased ERα in membrane fractions containing EGFR. More recent information from this group shows the in-vivo relevance of the ERα–striatin complex [39▪▪]. In-vivo blockade of the ER–striatin complex was performed using a novel mouse model that was created to produce a blocking peptide against the complex. The authors demonstrate loss of oestrogen-mediated protection against vascular injury following carotid artery wire injury in these mice.

The association between ERα and striatin raises the possibility that striatin may be a mediator of the rapid/nongenomic effects of other steroids. To this end, we recently reported that activation of mineralocorticoid receptor leads to increases of striatin levels in the vasculature and that the mineralocorticoid receptor is likewise complexed with cav-1 and striatin in vascular tissue (Fig. 1) [40▪]. We determined the in-vivo effects of salt restriction on striatin levels in vascular tissue that were associated with increased striatin levels in heart, aorta and kidneys. Our results also show that striatin is present and coprecipitates with the mineralocorticoid receptor in mouse aortas, heart and endothelial cells. Of importance, we have reported that aldosterone in vitro can stimulate increases of striatin mRNA and protein levels in both human and mouse endothelial cells, events that are not observed when cells are incubated with oestrogen. The in-vivo relevance of these studies was confirmed using two mouse models of mineralocorticoid receptor activation. We studied two previously described mouse models of increased aldosterone levels: intraperitoneal aldosterone administration and a model of chronic aldosterone mediated cardiovascular damage following treatment with N(G)-nitro-L-arginine methyl ester along with angiotensin II. In both models, we observed increased abundance of striatin protein in heart tissue. These results provide evidence further supporting the contention that striatin is an important component of mineralocorticoid receptor activation in the cardiovascular system.

Other than the work of the Karas group and Romero's group, there remains little information on the physiological role of striatin in the cardiovascular system. Transcriptional profiling of heart tissue has revealed the presence of striatin [41]. Meurs et al. [42] localized striatin to the intercalated discs within cardiac myocytes from boxer dogs. They also identified a deletion in the 3’ untranslated region of the STRN gene that was associated with arrhythmogenic right ventricular cardiomyopathy in these dogs, which was associated with reduced striatin expression and protein levels. However, much more remains to be done to thoroughly comprehend the role of striatin in the cardiovascular system. Taken together, the available evidence would suggest that striatin mediates a novel level of interaction between signalling molecules, steroids and the cardiovascular system that may be important to understand steroid function in the vasculature.

Back to Top | Article Outline


The recent literature summarized above underlines the emergent roles of LSD1, cav-1 and striatin in modulating aldosterone's pathways resulting in salt sensitivity of BP. Clearly, further studies are needed to elucidate the relevance of these molecules as markers of aldosterone/mineralocorticoid receptor activation in humans. Furthermore, these biomarkers may identify new molecular pathways involved in hypertension, thus improving our current strategies for treatment and prevention.

Back to Top | Article Outline


This work was supported in part by grants from the National Institutes of Health: HL104032, HL096518, RM-07-2002, T32 HL007609, HL086907, HL094452, HL085224; The Chilean National Science and Technology Research Fund 1130427 and The William F. Milton Fund Faculty Award, Harvard Medical School.

Back to Top | Article Outline

Conflicts of interest

There are no conflicts of interest.

Back to Top | Article Outline


Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
Back to Top | Article Outline


1▪. Simino J, Rao DC, Freedman BI. Novel findings and future directions on the genetics of hypertension. Curr Opin Nephrol Hypertens 2012; 21:500–507.

An outstanding review of the future directions of genetic studies in hypertension.

2. Cowley AW Jr, Nadeau JH, Baccarelli A, et al. Report of the National Heart, Lung, and Blood Institute Working Group on epigenetics and hypertension. Hypertension 2012; 59:899–905.
3. Millis RM. Epigenetics and hypertension. Curr Hypertens Rep 2011; 13:21–28.
4▪▪. Zhang LN, Liu PP, Wang L, et al. Lower ADD1 gene promoter DNA methylation increases the risk of essential hypertension. PLoS One 2013; 8:e63455.

A key study demonstrating epigenetic changes in promoter DNA methylation of α-adducin (ADD1) gene in the pathogenesis of essential hypertension.

5. Grant FD, Romero JR, Jeunemaitre X, et al. Low-renin hypertension, altered sodium homeostasis, and an alpha-adducin polymorphism. Hypertension 2002; 39:191–196.
6. Liu K, Liu J, Huang Y, et al. Alpha-adducin Gly460Trp polymorphism and hypertension risk: a meta-analysis of 22 studies including 14303 cases and 15961 controls. PLoS One 2010; 5:e13057.
7. Li YY. alpha-Adducin Gly460Trp gene mutation and essential hypertension in a Chinese population: a meta-analysis including 10,960 subjects. PLoS One 2012; 7:e30214.
8. Ding Y, Lv J, Mao C, et al. High-salt diet during pregnancy and angiotensin-related cardiac changes. J Hypertens 2010; 28:1290–1297.
9. Xu X, Su S, Barnes VA, et al. A genome-wide methylation study on obesity: differential variability and differential methylation. Epigenetics 2013; 8:522–533.
10. Ronn T, Volkov P, Davegardh C, et al. A six months exercise intervention influences the genome-wide DNA methylation pattern in human adipose tissue. PLoS Genet 2013; 9:e1003572.
11. Williams GH, Hollenberg NK. Sodium-sensitive essential hypertension: emerging insights into an old entity. J Am Coll Nutr 1989; 8:490–494.
12. Chamarthi B, Williams JS, Williams GH. A mechanism for salt-sensitive hypertension: abnormal dietary sodium-mediated vascular response to angiotensin-II. J Hypertens 2010; 28:1020–1026.
13. El Shamieh S, Visvikis-Siest S. Genetic biomarkers of hypertension and future challenges integrating epigenomics. Clin Chim Acta 2012; 414:259–265.
14. Pojoga LH, Williams JS, Yao TM, et al. Histone demethylase LSD1 deficiency during high-salt diet is associated with enhanced vascular contraction, altered NO-cGMP relaxation pathway, and hypertension. Am J Physiol Heart Circ Physiol 2011; 301:H1862–H1871.
15▪▪. Williams JS, Chamarthi B, Goodarzi MO, et al. Lysine-specific demethylase 1: an epigenetic regulator of salt-sensitive hypertension. Am J Hypertens 2012; 25:812–817.

A seminal translational study describing the role of LSD-1 as a crucial epigenetic regulator of salt sensitivity of BP in both human and rodents.

16. Shi Y. Histone lysine demethylases: emerging roles in development, physiology and disease. Nat Rev Genet 2007; 8:829–833.
17▪. Krug AW, Tille E, Sun B, et al. Lysine-specific demethylase-1 modifies the age effect on blood pressure sensitivity to dietary salt intake. Age (Dordr) 2013; 35:1809–1820.

An interesting study that highlights the important interaction between ageing, epigenetic changes and environment.

18. Mu S, Shimosawa T, Ogura S, et al. Epigenetic modulation of the renal beta-adrenergic-WNK4 pathway in salt-sensitive hypertension. Nat Med 2011; 17:573–580.
19. Krug AW, Pojoga LH, Williams GH, Adler GK. Cell membrane-associated mineralocorticoid receptors? New evidence. Hypertension 2011; 57:1019–1025.
20. Ricchiuti V, Lapointe N, Pojoga L, et al. Dietary sodium intake regulates angiotensin II type 1, mineralocorticoid receptor, and associated signaling proteins in heart. J Endocrinol 2011; 211:47–54.
21. Gildea JJ, Kemp BA, Howell NL, et al. Inhibition of renal caveolin-1 reduces natriuresis and produces hypertension in sodium-loaded rats. Am J Physiol Renal Physiol 2011; 300:F914–F920.
22. Pojoga LH, Adamova Z, Kumar A, et al. Sensitivity of NOS-dependent vascular relaxation pathway to mineralocorticoid receptor blockade in caveolin-1-deficient mice. Am J Physiol Heart Circ Physiol 2010; 298:H1776–H1788.
23. Pojoga LH, Romero JR, Yao TM, et al. Caveolin-1 ablation reduces the adverse cardiovascular effects of N-omega-nitro-L-arginine methyl ester and angiotensin II. Endocrinology 2010; 151:1236–1246.
24. Pojoga LH, Yao TM, Sinha S, et al. Effect of dietary sodium on vasoconstriction and eNOS-mediated vascular relaxation in caveolin-1-deficient mice. Am J Physiol Heart Circ Physiol 2008; 294:H1258–H1265.
25. Nakamura T, Fukuda M, Kataoka K, et al. Eplerenone potentiates protective effects of amlodipine against cardiovascular injury in salt-sensitive hypertensive rats. Hypertens Res 2011; 34:817–824.
26. Sowa G. Caveolae, caveolins, cavins, and endothelial cell function: new insights. Front Physiol 2012; 2:120.
27. van Dokkum RP, Buikema H. Possible new druggable targets for the treatment of nephrosis. Perhaps we should find them in caveolae? Curr Opin Pharmacol 2009; 9:132–138.
28. Fujita T. Mineralocorticoid receptors, salt-sensitive hypertension, and metabolic syndrome. Hypertension 2010; 55:813–818.
29. Shibata S, Nagase M, Yoshida S, et al. Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease. Nat Med 2008; 14:1370–1376.
30. Nethe M, Anthony EC, Fernandez-Borja M, et al. Focal-adhesion targeting links caveolin-1 to a Rac1-degradation pathway. J Cell Sci 2010; 123:1948–1958.
31. Lee IH, Campbell CR, Song SH, et al. The activity of the epithelial sodium channels is regulated by caveolin-1 via a Nedd4-2-dependent mechanism. J Biol Chem 2009; 284:12663–12669.
32. Li X, McClellan ME, Tanito M, et al. Loss of caveolin-1 impairs retinal function due to disturbance of subretinal microenvironment. J Biol Chem 2012; 287:16424–16434.
33. Morrill GA, Kostellow AB, Askari A. Caveolin-Na/K-ATPase interactions: role of transmembrane topology in nongenomic steroid signal transduction. Steroids 2012; 77:1160–1168.
34. Park JH, Ryu JM, Yun SP, et al. Fibronectin stimulates migration through lipid raft dependent NHE-1 activation in mouse embryonic stem cells: involvement of RhoA, Ca(2+)/CaM, and ERK. Biochim Biophys Acta 2012; 1820:1618–1627.
35▪. Ares GR, Ortiz PA. Dynamin2, clathrin, and lipid rafts mediate endocytosis of the apical Na/K/2Cl cotransporter NKCC2 in thick ascending limbs. J Biol Chem 2012; 287:37824–37834.

A key study documenting that cav-1 silencing by shRNA in the rat kidney decreases the rate of NKCC2 endocytosis, consistent with a key role for cav-1 in renal sodium handling.

36. Tajima N, Itokazu Y, Korpi ER, et al. Activity of BK(Ca) channel is modulated by membrane cholesterol content and association with Na+/K+-ATPase in human melanoma IGR39 cells. J Biol Chem 2011; 286:5624–5638.
37. Gordon J, Hwang J, Carrier KJ, et al. Protein phosphatase 2a (PP2A) binds within the oligomerization domain of striatin and regulates the phosphorylation and activation of the mammalian Ste20-Like kinase Mst3. BMC Biochem 2011; 12:54.
38. Lu Q, Pallas DC, Surks HK, et al. Striatin assembles a membrane signaling complex necessary for rapid, nongenomic activation of endothelial NO synthase by estrogen receptor alpha. Proc Natl Acad Sci U S A 2004; 101:17126–17131.
39▪▪. Bernelot Moens SJ, Schnitzler GR, Nickerson M, et al. Rapid estrogen receptor signaling is essential for the protective effects of estrogen against vascular injury. Circulation 2012; 126:1993–2004.

Using a novel mouse model, these investigators documented the effect on vascular injury in an in-vivo study when the interaction between striatin and oestrogen receptor-α is blocked.

40▪. Pojoga LH, Coutinho P, Rivera A, et al. Activation of the mineralocorticoid receptor increases striatin levels. Am J Hypertens 2012; 25:243–249.

A key study providing evidence that mineralocorticoid receptor activation leads to increases in the scaffolding protein striatin, both in vivo and in vitro.

41. Yanai I, Benjamin H, Shmoish M, et al. Genome-wide midrange transcription profiles reveal expression level relationships in human tissue specification. Bioinformatics 2005; 21:650–659.
42. Meurs KM, Mauceli E, Lahmers S, et al. Genome-wide association identifies a deletion in the 3’ untranslated region of striatin in a canine model of arrhythmogenic right ventricular cardiomyopathy. Hum Genet 2010; 128:315–324.

aldosterone; caveolin 1; lysine-specific demethylase 1; mineralocorticoid receptor striatin

Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.