Mineralocorticoid receptor blockade protects from angiotensin II-induced target-organ damage. 11beta-Hydroxysteroid dehydrogenase type 2 protects the mineralocorticoid receptor from activation by glucocorticoids; however, high glucocorticoid concentrations and absent 11beta-hydroxysteroid dehydrogenase type 2 in some tissues make glucocorticoids highly relevant mineralocorticoid receptor ligands. We investigated the effects of corticosterone (10(-6) to 10(-12) mol/L) on early vascular mineralocorticoid receptor signaling by Western blotting, confocal microscopy, and myography. Corticosterone initiated extracellular signal-regulated kinase 1/2 phosphorylation in rat vascular smooth muscle cells at >/=10(-11) mol/L doses. Protein synthesis inhibitors had no effect, indicating a nongenomic action. Corticosterone also stimulated c-Jun N-terminal kinase, p38, Src, and Akt phosphorylation at 15 minutes and enhanced angiotensin II-induced signaling at 5 minutes. A specific epidermal growth factor receptor blocker, AG1478, as well as the Src inhibitor PP2, markedly reduced corticosterone-induced extracellular signal-regulated kinase 1/2 phosphorylation, as did preincubation of cells with the mineralocorticoid receptor antagonist spironolactone. Silencing mineralocorticoid receptor with small interfering RNA abolished corticosterone-induced effects. Corticosterone (10(-9) mol/L) enhanced phenylephrine-induced contraction of intact aortic rings. These effects were dependent on the intact endothelium, mineralocorticoid receptor, and mitogen-activated protein kinase kinase 1/extracellular signal-regulated kinase signaling. We conclude that corticosterone induces rapid mineralocorticoid receptor signaling in vascular smooth muscle cells that involves mitogen-activated protein kinase kinase/extracellular signal-regulated kinase-dependent pathways. These new mineralocorticoid receptor-dependent signaling pathways suggest that glucocorticoids may contribute to vascular disease via mineralocorticoid receptor signaling, independent of circulating aldosterone.

Molnar GA, Lindschau C, Dubrovska G, Mertens PR, Kirsch T, Quinkler M, Gollasch M, Wresche S, Luft FC, Muller DN, Fiebeler A.

Medical Faculty of the Charité, Experimental and Clinical Research Center and Max Delbrück Center, Franz Volhard Clinic, HELIOS Klinikum-Berlin, Berlin, Germany; Department of Nephrology and Clinical Immunology, University Hospital Rheinisch-Westfälische Technische Hochschule-Aachen, Aachen, Germany; Department of Internal Medicine-Nephrology, Hannover University Medical School, Hannover, Germany; 2nd Department of Medicine and Nephrological Center, University of Pecs, Pecs, Hungary; Section Nephrology/Intensive Care, Campus Virchow, Charité, Berlin, Germany; Section Clinical Endocrinology, Campus Mitte, Charité, Berlin, Germany.