Activation of the aldosterone/mineralocorticoid receptor system in chronic kidney disease and metabolic syndrome

Abstract

Recent clinical and experimental studies have shown that aldosterone is a potent inducer of proteinuria and that mineralocorticoid receptor (MR) antagonists confer efficient antiproteinuric effects. We identified glomerular epithelial cells (podocytes) as novel targets of aldosterone; activation of MR injures podocytes possibly via oxidative stress, resulting in disruption of glomerular filtration barrier, proteinuria, and progression of chronic kidney disease. We also demonstrated that SHR/cp, a rat model of metabolic syndrome, was susceptible to podocyte injury and proteinuria. Aldosterone excess caused by adipocyte-derived aldosterone-releasing factors was suggested to underlie the nephropathy. High salt intake augmented MR activation in the kidney and exacerbated the nephropathy. Furthermore, we identified an alternative pathway of MR activation by small GTPase Rac1. RhoGDIalpha knockout mice, a model with Rac1 activation in the kidney, showed albuminuria, podocyte injury, and glomerulosclerosis. Renal injury in the knockout mice was accompanied by enhanced MR signaling in the kidney despite normoaldosteronemia, and was ameliorated by an MR antagonist, eplerenone. Moreover, Rac-specific inhibitor significantly reduced the nephropathy, concomitantly with repression of MR activation. In vitro transfection studies provided direct evidence of Rac1-mediated MR activation. In conclusion, our findings suggest that MR activation plays a pivotal role in the pathogenesis of chronic kidney disease in metabolic syndrome, and that MR may be activated both aldosterone dependently (via aldosterone-releasing factors) and independently (via Rac1). MR antagonists are promising antiproteinuric drugs in metabolic syndrome, although long-term effects on renal outcomes, mortality, and safety need to be established.

The aldosterone receptor antagonist spironolactone prevents peritoneal inflammation and fibrosis

“…33 We found that MR and CYP11B2 expression was enhanced in the peritoneum. CYP11B2 is a key factor in aldosterone synthesis.…”

Biphasic Time Course of the Changes in Aldosterone Biosynthesis Under High-Salt Conditions in Dahl Salt-Sensitive Rats

“…In addition, the intra-adrenal RAS is highly sensitive to a variety of stressors, such as chronic salt overload and metabolic disorders. 33 In the clinical setting, paradoxical increase in aldosterone biosynthesis emerges in hypertensive or heart failure patients treated with AT 1 receptor antagonists or angiotensin-converting enzyme inhibitors. These observations suggest that there could also exist the RAS-independent stimulation of adrenal aldosterone production in some pathological conditions.…”

Ginsenoside Rg1 protects mouse podocytes from aldosterone-induced injury in vitro

“…Aldosterone levels increase in hypertension, DN, and chronic kidney disease [7][8][9] . In addition to its hemodynamic effects, the local effects of aldosterone on renal cells, including proximal tubular cells, mesangial cells, and podocytes, are currently being studied, and accumulating evidence suggests that aldosterone plays a pathogenic role in renal injury, leading to severe proteinuria and glomerular injury [10] .…”