11-dehydrocorticosterone and Body-Weight

Aldosterone induces fibrotic changes in cardiovascular tissues but its effects have usually been demonstrated in models of pre-existing renal injury and/or hypertension. This study tests the hypothesis that aldosterone can directly induce vascular fibrotic changes in the absence of prior renal injury or hypertension. Experiments were conducted in intact or adrenalectomized (ADX) mice. Mice were divided into groups and treated for 1 week with vehicle or aldosterone (8 μg/kg/day)± inhibitor (800 μg/kg/day): CONTROLS, mice treated with aldosterone, ADX-CONTROLS, ADX+corticosterone (CORT 8 μg/kg/day), ADX with aldosterone, ADX with aldosterone plus the mineralocorticoid receptor (MR) antagonist RU-318, ADX with aldosterone+CORT (CORT inhibitor dose), and ADX with aldosterone+11-dehydro-CORT. Aortic smooth muscle to collagen ratio, aorta intimal thickness (μm), heart weight/body weight ratio (mg/gm), and left ventricular collagen (%) were measured. Prior to sacrifice, blood pressures were normal in all animals. Lower dose CORT alone had no effect on any of the variables examined. Aldosterone exposure was associated with extra-cellular matrix accumulation in cardiovascular tissues in intact mice and adrenalectomy exacerbated these effects. RU-318, CORT (inhibitor dose), and 11-deydro-CORT each attenuated the early fibrotic changes induced by aldosterone. In the heart, aldosterone exposure affected all the parameters measured and caused intimal hypercellularity with monocytes adhering to endothelial cells lining coronary vessels. Cultured endothelial cells exposed to aldosterone (10nM) released E-selectin, produced collagen, and promoted monocyte adhesion. These effects were inhibited by RU-318 and 11-deydro-CORT but not by CORT. Thus, adrenalectomy enhances aldosterone induced early fibrotic changes in heart and aorta. Aldosterone initially targets vascular endothelial cells. MR antagonists and 11-dehydro-CORT, an 11β-HSD dehydrogenase end-product, directly attenuate these effects.

Topics: Adrenal Glands; Adrenalectomy; Aldosterone; Animals; Aorta; Blood Pressure; Body Weight; Cell Adhesion; Collagen; Corticosterone; E-Selectin; Gene Expression; Heart; Human Umbilical Vein Endothelial Cells; Humans; Male; Mice; Mice, Inbred C57BL; Mineralocorticoid Receptor Antagonists; Monocytes; Tunica Intima

Glycyrrhetinic acid (GA) inhibits 11beta-hydroxysteroid dehydrogenase and increases the levels and thus the action of endogenous glucocorticoid. We considered that GA could be used effectively for treatment of autoimmune diseases that have been treated by synthetic glucocorticoids. In this report, we demonstrated that GA delayed the development of autoimmune disease in spontaneously autoimmune strain MRL lpr/lpr (referred to as lpr) mice. GA was administered via drinking water at approximately 5 mg/kg/day for 170 days. An increase of urine protein levels in the mice treated with GA was delayed as compared to the control mice. After GA treatment began, urinary protein levels in the GA-treated mice were found to be significantly lower than vehicle-treated mice (p<0.05) between days 18 to 50. At 3 weeks of GA treatment serum IgG levels were lowered significantly in comparison with the control mice (p<0.03). In this circumstance, 11beta-HSD activities in liver and kidney were significantly inhibited by GA treatment (p<0.03, p<0.04 respectively). Concentration of corticosterone and dehydrocorticosterone in liver significantly increased after 3 weeks of GA treatment (p<0.02, p<0.01 respectively). In contrast to the local tissue levels of corticosteroids, the serum concentration of dehydrocorticosterone significantly decreased with GA treatment (p<0.02). These data suggest that GA could modify the local and systemic homeostasis of steroid metabolism in lpr mice. We concluded that the continuous treatment of GA is able to retard the development of autoimmune disease by suppressing urinary protein excretion and serum IgG levels in lpr mice. Modulation of local tissue levels as well as serum levels of corticosteroid by GA may thus be implicated in the therapeutic efficacy of GA.

Topics: 11-beta-Hydroxysteroid Dehydrogenases; Administration, Oral; Animals; Autoimmune Diseases; Body Weight; Corticosterone; Disease Models, Animal; Enzyme Inhibitors; Glycyrrhetinic Acid; Hydroxysteroid Dehydrogenases; Kidney; Liver; Male; Mice; Mice, Inbred MRL lpr; Organ Size; Water Supply