Aldosterone as a mediator of progressive renal dysfunction: evolving perspectives.
End-stage renal disease (ESRD) comprises an enormous public health burden, with an incidence and prevalence that are increasingly on the rise. This escalating prevalence suggests that newer therapeutic interventions and strategies are needed to complement current therapeutic approaches. Although much evidence demonstrates conclusively that angiotensin II mediates progressive renal disease, recent evidence also implicates aldosterone as an important pathogenetic factor in progressive renal disease. Recently, several lines of experimental evidence demonstrate that selective blockade of aldosterone, independent of renin-angiotensin blockade, reduces proteinuria and nephrosclerosis in the spontaneously hypertensive stroke-prone rat (SHRSP) model and reduces proteinuria and glomerulosclerosis in the subtotally nephrectomized rat model (ie, remnant kidney). Whereas pharmacologic blockade with angiotensin II receptor blockers and angiotensin-converting enzyme (ACE) inhibitors reduces proteinuria and nephrosclerosis/glomerulosclerosis, selective reinfusion of aldosterone restores these abnormalities despite continued renin-angiotensin blockade. Aldosterone may promote fibrosis by several mechanisms, including plasminogen activator inhibitor-1 (PAI-1) expression and consequent alterations of vascular ribrinolysis, by stimulation of transforming growth factor-beta1 (TGF-beta1), and by stimulation of reactive oxygen species (ROS). Based on this formulation, randomized clinical studies will be initiated to delineate the potential renal-protective effects of aldosterone receptor blockade.
Epstein
M
M
Department of Medicine, University of Miami School of Medicine, Florida, USA.
D000450:Aldosterone / Q000378:metabolism*; D000818:Animals; D002986:Clinical Trials as Topic; D018450:Disease Progression; D006801:Humans; D015994:Incidence; D007676:Kidney Failure, Chronic / Q000378:metabolism / Q000503:physiopathology*; D000451:Mineralocorticoid Receptor Antagonists; D023421:Models, Animal; D015995:Prevalence; D012084:Renin-Angiotensin System
D000451:Mineralocorticoid Receptor Antagonists; D000450:Aldosterone