Contribution of aldosterone to cardiovascular and renal inflammation and fibrosis

Nat Rev Nephrol. 2013 Aug;9(8):459-69. doi: 10.1038/nrneph.2013.110. Epub 2013 Jun 18.

Abstract

The steroid hormone aldosterone regulates sodium and potassium homeostasis. Aldosterone and activation of the mineralocorticoid receptor also causes inflammation and fibrosis of the heart, fibrosis and remodelling of blood vessels and tubulointerstitial fibrosis and glomerular injury in the kidney. Aldosterone and mineralocorticoid-receptor activation initiate an inflammatory response by increasing the generation of reactive oxygen species by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and mitochondria. High salt intake potentiates these effects, in part by activating the Rho family member Rac1, a regulatory subunit of reduced NADPH oxidase that activates the mineralocorticoid receptor. Studies in mice in which the mineralocorticoid receptor has been deleted from specific cell types suggest a key role for macrophages in promoting inflammation and fibrosis. Aldosterone can exert mineralocorticoid-receptor-independent effects via the angiotensin II receptor and via G-protein-coupled receptor 30. Mineralocorticoid-receptor antagonists are associated with decreased mortality in patients with heart disease and show promise in patients with kidney injury, but can elevate serum potassium concentration. Studies in rodents genetically deficient in aldosterone synthase or treated with a pharmacological aldosterone-synthase inhibitor are providing insight into the relative contribution of aldosterone compared with the contribution of mineralocorticoid-receptor activation in inflammation, fibrosis, and injury. Aldosterone-synthase inhibitors are under development in humans.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Aldosterone / physiology*
  • Animals
  • Aromatase Inhibitors / pharmacology
  • Cardiovascular System / physiopathology*
  • Cytochrome P-450 CYP11B2 / deficiency
  • Cytochrome P-450 CYP11B2 / genetics
  • Endothelial Cells / metabolism
  • Fadrozole / pharmacology
  • Fibrosis
  • Humans
  • Imidazoles / pharmacology
  • Inflammation / physiopathology
  • Kidney / physiopathology*
  • Macrophages / physiology
  • Mineralocorticoid Receptor Antagonists / pharmacology
  • Myocardium / pathology*
  • Myocytes, Cardiac / metabolism
  • Pyridines / pharmacology
  • Reactive Oxygen Species / metabolism
  • Receptors, Mineralocorticoid / metabolism
  • Sodium, Dietary / adverse effects

Substances

  • Aromatase Inhibitors
  • Imidazoles
  • Mineralocorticoid Receptor Antagonists
  • Pyridines
  • Reactive Oxygen Species
  • Receptors, Mineralocorticoid
  • Sodium, Dietary
  • Aldosterone
  • Osilodrostat
  • Cytochrome P-450 CYP11B2
  • Fadrozole