Mineralocorticoid and SGK1-sensitive inflammation and tissue fibrosis.
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 TH17 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.
Department of Internal Medicine, University of Tübingen, Tübingen, Germany.
Ferruh
F
Artunc
Florian
F
Lang
D000818:Animals; D005355:Fibrosis / Q000209:etiology; D007249:Inflammation / Q000209:etiology*; D051379:Mice; D008901:Mineralocorticoids / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D051381:Rats; D018161:Receptors, Mineralocorticoid / Q000502:physiology; D058504:Th17 Cells / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology; D015854:Up-Regulation
D008901:Mineralocorticoids; D018161:Receptors, Mineralocorticoid; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases