Mineralocorticoid and SGK1-Sensitive Inflammation and Tissue Fibrosis

Mineralocorticoids are decisive hormones in the regulation of extracellular volume homeostasis [1,2,3]. 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]. The present brief synopsis addresses the role of mineralocorticoids in the regulation of inflammation and tissue fibrosis. Specific emphasis will be placed on the role of the serum- and glucocorticoid-inducible kinase 1 (SGK1) in the mineralocorticoid action on inflammation and fibrosis. The reader is encouraged to consult earlier, more extensive reviews on mineralocorticoids and inflammation as well as tissue fibrosis [8,9,10,11,12,13,14,15,16,17].

Mineralocorticoid and salt excess in rats lead to the activation of T_H17-helper cells in several tissues including the heart and kidneys [18]. The T_H17-helper cells upregulate the pro-inflammatory cytokines GM-CSF, TNF-α and interleukin (IL)-2 [19]. The effect of mineralocorticoids on T_H17 cell abundance is reversed by spironolactone treatment [18]. Application of anti-IL-17 to mineralocorticoid/salt-treated rats blunts the arterial hypertension, renal and cardiac expression of profibrotic and pro-inflammatory mediators as well as collagen deposition [18]. Mineralocorticoids further amplify activation of blood platelets [20], which in turn participate in vascular inflammation [21,22].

The mineralocorticoid receptor is expressed in vascular smooth muscle cells and participates in vascular remodeling [23]. Mechanisms involved in mineralocorticoid regulation of vascular function include generation of reactive oxygen species by nicotinamide adenine dinucleotide phosphate oxidase and by mitochondria [24,25], Rho-kinase signaling [23,25,26], activation of epidermal growth factor receptor [27], stimulation of vascular endothelial growth factor type 1 receptor [23] and galectin signaling [23]. Mineralocorticoids are effective by influencing both genomic and nongenomic mechanisms [28].

Mineralocorticoids stimulate vascular [10,23,24,29,30,31], cardiac [8,24,29,32,33,34,35,36,37,38,39,40], renal [24,26,36,41,42,43], peritoneal [14,17] and pancreatic [44] fibrosis.

The inflammatory signaling of mineralocorticoids involves SGK1 [7,45]. Mineralocorticoids are strong stimulators of SGK1 expression [46] and stimulate the phosphoinositide 3-kinase pathway [47,48], which in turn activates SGK1 [46]. SGK1 expression is further upregulated by an increase in extracellular NaCl concentration [45,49,50], an effect involving p38/MAPK [46]. The kinase inactivates the transcription factor Foxo1, which is in turn required for IL-23 receptor expression [50]. Via this receptor, IL-23 stimulates the generation of IL-17-producing CD4⁺-helper T cells (T_H17 cells). The T_H17 cells play a decisive role in autoimmune disease [19]. T_H17 cells are further upregulated by increased extracellular NaCl concentration [50], an effect involving p38/MAPK, SGK1 and nuclear factor of activated T cells 5 (NFAT5, TONEBP) [19]. Along those lines, high-salt diet fosters the infiltration of T_H17 cells into the central nervous system and thus aggravates the course of experimental autoimmune encephalomyelitis [19]. At least in theory, mineralocorticoid excess may thus through upregulation of SGK1 predispose to autoimmune disease.

SGK1 is decisive for mineralocorticoid- and high-salt-induced tissue fibrosis [41,51]. Accordingly, gene-targeted mice lacking functional SGK1 are largely protected against cardiac [51] and renal [41] fibrosis following mineralocorticoid excess. Excessive SGK1 expression is observed in a wide variety of fibrosing tissues, such as lung fibrosis, diabetic nephropathy, glomerulonephritis, experimental nephrotic syndrome, obstructive nephropathy, liver cirrhosis, fibrosing pancreatitis, peritoneal fibrosis, Crohn's disease and celiac disease [41,45,46,51,52,53]. SGK1 expression is upregulated by transforming growth factor β (TGF-β) [46], a powerful stimulator of tissue fibrosis [11,54,55,56,57,58,59]. The fibrosing effect of TGF-β is partially mediated by upregulation of the transcription factors Smad2/3 [45]. Those transcription factors are degraded by the ubiquitin ligase Nedd4L [7,45]. Nedd4L is phosphorylated and thus inactivated by SGK1, which thus amplifies the TGF-β effects [45]. SGK1 further activates nuclear factor-κB (NFκB) [46], a transcription factor fostering inflammation and fibrosis [45,60,61]. SGK1 phosphorylates and thus activates the kinase IKK, which in turn phosphorylates the NFκB inhibitory protein IκB [46,51]. The phosphorylation triggers the degradation of IκB, thus leading to disinhibition and nuclear translocation of NFκB [46,51]. NFκB-sensitive genes include connective tissue growth factor (CTGF), which is involved in fibrosis [46,51]. SGK1-dependent expression of CTGF contributes to the mineralocorticoid stimulation of cardiac fibrosis [46,51] and aging of the skin [62]. SGK1 is further involved in angiotensin II-induced cardiac CTGF formation and fibrosis [63,64] as well as in cardiac remodeling following increased afterload [45,65,66].

Mineralocorticoid-induced inflammation and tissue fibrosis is blunted or even reversed by inhibitors of the mineralocorticoid receptor, such as spironolactone or eplerenone [29,42,67,68,69,70,71,72,73]. At least in theory, untoward mineralocorticoid effects could be abrogated by interference with mineralocorticoid receptor-dependent signaling, such as inhibition of SGK1 [74]. In view of the existing knowledge, it is tempting to speculate that mineralocorticoid receptor blockade or inhibition of mineralocorticoid receptor-dependent signaling favorably influences the clinical course of autoimmune and fibrosing disease.