Aldosterone, hypertension and heart failure: insights from clinical trials

Funder, John W.

doi:10.1038/hr.2010.115

Cited by 30 publications

(19 citation statements)

References 22 publications

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“…They are released following extracellular volume depletion and restore extracellular volume by stimulating salt intake [4,5] and curtailing renal salt loss [2]. Extracellular volume expansion increases cardiac output and thus blood pressure [1,6]. However, mineralocorticoids participate in the regulation of a wide variety of further functions [7].…”

Section: Introductionmentioning

confidence: 99%

Mineralocorticoid and SGK1-Sensitive Inflammation and Tissue Fibrosis

Artunc¹,

Läng

2014

Nephron Physiol

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Effects of mineralocorticoids are not restricted to regulation of epithelial salt transport, extracellular volume and blood pressure; mineralocorticoids also influence a wide variety of seemingly unrelated functions such as inflammation and fibrosis. The present brief review addresses the role of mineralocorticoids in the orchestration of these latter processes. Mineralocorticoids foster inflammation as well as vascular, cardiac, renal and peritoneal fibrosis. Mechanisms involved in mineralocorticoid-sensitive inflammation and fibrosis include the serum- and glucocorticoid-inducible kinase 1 (SGK1), which is genomically upregulated by mineralocorticoids and transforming growth factor β (TGF-β), and stimulated by mineralocorticoid-sensitive phosphatidylinositide 3-kinase. SGK1 upregulates the inflammatory transcription factor nuclear factor-κB, which in turn stimulates the expression of diverse inflammatory mediators including connective tissue growth factor. Moreover, SGK1 inhibits the degradation of the TGF-β-dependent transcription factors Smad2/3. Mineralocorticoids foster the development of T_H17 cells, which is compromised following SGK1 deletion. Excessive SGK1 expression is observed in a wide variety of fibrosing diseases including lung fibrosis, diabetic nephropathy, glomerulonephritis, obstructive kidney disease, experimental nephrotic syndrome, obstructive nephropathy, liver cirrhosis, fibrosing pancreatitis, peritoneal fibrosis, Crohn's disease and celiac disease. The untoward inflammatory and fibrosing effects of mineralocorticoids could be blunted or even reversed by mineralocorticoid receptor blockers, which may thus be considered in the treatment of inflammatory and/or fibrosing disease.

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Section: Introductionmentioning

confidence: 99%

Mineralocorticoid and SGK1-Sensitive Inflammation and Tissue Fibrosis

Artunc¹,

Läng

2014

Nephron Physiol

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“…Enhanced salt intake and renal salt retention lead to extracellular volume expansion with increase of blood pressure [7,8,22]. The effect of mineralocorticoids on blood pressure does, however, not depend on the effect of mineralocorticoids on the distal nephron [23] but is attributed in part to vascular inflammation [24,25], to enhanced endothelial stiffness, which compromises the release of nitric oxide [26,27,28,29,30] and direct effects of the mineralocorticoid receptor in vascular smooth muscle [31].…”

Section: Effects Of Mineralocorticoidsmentioning

confidence: 99%

“…Moreover, mineralocorticoids curtail salt loss by stimulating salt (re)absorption in colon [5,6], sweat glands and salivary glands [6]. At least in part due to extracellular volume expansion, mineralocorticoids enhance cardiac output and blood pressure [7,8]. However, the mineralocorticoid receptor [9,10,11] is expressed in a wide variety of tissues [10].…”

Section: Introductionmentioning

confidence: 99%

On the Pleotropic Actions of Mineralocorticoids

Läng

2014

Nephron Physiol

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Classical effects of mineralocorticoids include stimulation of Na⁺ reabsorption and K⁺ secretion in the kidney and other epithelia including colon and several glands. Moreover, mineralocorticoids enhance the excretion of Mg²⁺ and renal tubular H⁺ secretion. The renal salt retention following mineralocorticoid excess leads to extracellular volume expansion and hypertension. The increase of blood pressure following mineralocorticoid excess is, however, not only the result of volume expansion but may result from stiff endothelial cell syndrome impairing the release of vasodilating nitric oxide. Beyond that, mineralocorticoids are involved in the regulation of a wide variety of further functions, including cardiac fibrosis, platelet activation, neuronal function and survival, inflammation as well as vascular and tissue fibrosis and calcification. Those functions are briefly discussed in this short introduction to the special issue. Beyond that, further contributions of this special issue amplify on mineralocorticoid-induced sodium appetite and renal salt retention, the role of mineralocorticoids in the regulation of acid-base balance, the involvement of aldosterone and its receptors in major depression, the mineralocorticoid stimulation of inflammation and tissue fibrosis and the effect of aldosterone on osteoinductive signaling and vascular calcification. Clearly, still much is to be learned about the various ramifications of mineralocorticoid-sensitive physiology and pathophysiology.

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“…Mineralocorticoids have been shown to upregulate pendrin expression not only in kidney [14,18], but in heart, lung and thyroid as well [28]. Mineralocorticoid receptors are expressed in many tissues [29], such as kidney, colon, heart, lung, blood vessels, adipose tissue, thyroid and hippocampus [30,31,32,33,34,35], and mineralocorticoids participate in the regulation of diverse functions, such as renal and colonic Na + and K + transport [34], salt appetite [36], blood pressure [37], cardiac remodelling and fibrosis [38,39,40,41], endothelial stiffness [42,43], vascular stiffness [44], tissue calcification [45,46], as well as apoptosis in hippocampal neurons [47]. Along those lines, aldosterone influences expression of a wide variety of genes [38,39,44,46,48,49,50].…”

Section: Introductionmentioning

confidence: 99%

Sgk1 Sensitive Pendrin Expression in Murine Platelets

Pelzl

Fakhri²,

Umbach³

et al. 2013

Cell Physiol Biochem

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Background: The anion exchanger pendrin (SLC26A4) is required for proper development of the inner ear, and contributes to iodide organification in thyroid glands as well as anion transport in various epithelia, such as airways and renal tubules. SLC26A4 deficiency leads to Pendred syndrome, which is characterized by hearing loss with enlarged vestibular aqueducts and variable hypothyroidism and goiter. Pendrin expression in kidney, heart, lung and thyroid is up-regulated by the mineralocorticoid deoxycorticosterone (DOCA). Platelets express anion exchangers but virtually nothing is known about the molecular identity and regulation of those carriers. Other carriers such as the Na⁺/H⁺ exchanger are regulated by the mineralocorticoid-sensitive serum and glucocorticoid inducible kinase SGK1. Methods: The present study utilized i) quantitative reverse transcription polymerase chain reaction (RT-qPCR) to quantify the transcript levels of Slc26a4 as compared to Gapdh and ii) western blotting to assess Slc26a4 protein abundance in murine platelets from gene-targeted mice lacking Sgk1 (sgk1^-/-) and respective wild type animals (sgk1^+/+) treated without or with a subcutaneous injection of 2.5 mg DOCA for 3 h, or in sgk1^+/+ platelets with or without in vitro treatment for 1 h with 10 µg/ml DOCA. Results: Slc26a4 was expressed in platelets, and in vitro DOCA treatment increased Slc26a4 mRNA levels in platelets isolated from sgk1^+/+ mice. Moreover, in vivo DOCA treatment significantly up-regulated Slc26a4 mRNA levels in platelets isolated from sgk1^+/+ but not sgk1^-/- mice. An increase in Sgk1 mRNA levels paralleled that of Slc26a4 mRNA levels in platelets of sgk1^+/+ mice. In addition, DOCA treatment further increased Slc26a4 protein abundance in platelets isolated from sgk1^+/+ mice. Conclusions: Pendrin is expressed in platelets and is presumably regulated by SGK1 and mineralocorticoids.

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Aldosterone, hypertension and heart failure: insights from clinical trials

Cited by 30 publications

References 22 publications

Mineralocorticoid and SGK1-Sensitive Inflammation and Tissue Fibrosis

Mineralocorticoid and SGK1-Sensitive Inflammation and Tissue Fibrosis

On the Pleotropic Actions of Mineralocorticoids

Sgk1 Sensitive Pendrin Expression in Murine Platelets

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