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Contribution of aldosterone to cardiovascular and renal inflammation and fibrosis

Nature Reviews Nephrology volume 9, pages 459–469 (2013)Cite this article

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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.

Key Points

  • Aldosterone or mineralocorticoid-receptor activation trigger the formation of reactive oxygen species by NADPH oxidase and mitochondria that, in turn, induce a proinflammatory and profibrotic phenotype

  • Under conditions of high salt intake, Rac1 activates the mineralocorticoid receptor and increases the formation of reactive oxygen species

  • Aldosterone exerts rapid, transcription-independent effects (nongenomic effects) that may be mediated by G-protein-coupled receptor 30 and transactivation of the epithelial growth factor receptor

  • Studies in mice in which the mineralocorticoid receptor has been selectively deleted on specific cells indicate that systemic mineralocorticoid-receptor activation is not necessary to induce local inflammation and fibrosis

  • Aldosterone-synthase inhibition or deficiency prevents inflammation and fibrosis in many rodent models of cardiovascular or renal injury

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Figure 1: Mechanisms by which aldosterone and/or MR activation induce oxidative stress, inflammation, and fibrosis.
Figure 2: Effects of cell-specific activation of the MR.

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Acknowledgements

The author has received grant support from the National Institutes of Health (HL060906).

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  1. D-3100 Medical Center North, Vanderbilt University School of Medicine, Nashville, 37232, TN, USA

    Nancy J. Brown

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Nancy J. Brown has consulted for Novartis and received grant support from Shire Pharmaceutical and the National Institutes of Health.

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Brown, N. Contribution of aldosterone to cardiovascular and renal inflammation and fibrosis. Nat Rev Nephrol 9, 459–469 (2013). https://doi.org/10.1038/nrneph.2013.110

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