Mineralocorticoid and SGK1-Sensitive Inflammation and Tissue Fibrosis

Abstract

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.

Mineralocorticoid receptor associates with pro‐inflammatory bias in the hippocampus of spontaneously hypertensive rats

“…To investigate whether changes of microglia phenotype were accompanied by markers of neuroinflammation, we measured, by quantitative PCR, several molecules bound to inflammation and signalling in the hippocampus of the two strains. First, we determined SGK1, a determinant of mineralocorticoid and glucocorticoid function fostering inflammation in the periphery . In agreement with these effects, the hippocampus of SHR showed a five‐fold increase in Sgk1 mRNA compared to WKY rats ( P <.01) (Figure A).…”

“…Therefore, up‐regulation of Sgk1 in the hippocampus of SHR indicates that MR and GR are functionally active and may be involved in neuroinflammation. Proof of receptor activation is the increase of Sgk1 expression, a molecule genomically regulated by mineralocorticoids and glucocorticoids and involved in MR‐mediated inflammation . However, SGK1 plays other roles than inflammation because it is also implicated in the physiology and pathophysiology of sodium transport .…”

Dietary NaCl affects bleomycin-induced lung fibrosis in mice

“…[15] High dietary salt promotes pro-inflammatory T cells and Th17 inflammatory T cells, [11,15,66,67] and inhibits regulatory FOXP3 positive T cells differentiation and activation, [16] possibly through the regulation of the serine/threonine kinase serum glucocorticoid kinase 1 (SGK1). SGK1 has also been implicated in renal and cardiac fibrosis, [68] suggesting a mechanism by which high dietary salt drives multiple cell types to promote and maintain a pro-fibrotic response.…”

SGK1 induces vascular smooth muscle cell calcification through NF-κB signaling

“…As a matter of fact, mineralocorticoid receptor-sensitive upregulation of SGK1 expression has been shown to accelerate aging of the skin (48). SGK1 inhibition would further be expected to interfere with organ fibrosis, sodium reabsorption, metabolic syndrome, and thrombocyte aggregation as well as cardiac hypertrophy and failure (16,21,22,49). SGK1 inhibition may therefore prove a clinically effective treatment strategy and warrants further study of the translational potential.…”