Role of Rac1-mineralocorticoid-receptor signalling in renal and cardiac disease

Nat Rev Nephrol. 2013 Feb;9(2):86-98. doi: 10.1038/nrneph.2012.282. Epub 2013 Jan 8.

Abstract

The Rho-family small GTPase, Ras-related C3 botulinum toxin substrate 1 (Rac1), has been implicated in renal and cardiac disease. Rac1 activation in podocytes has been shown in several models of proteinuric kidney disease and a concept involving motile podocytes has been proposed. Evidence also exists for a critical role of Rac1-mediated oxidative stress in cardiac hypertrophy, cardiomyopathy and arrhythmia, and of the aldosterone-mineralocorticoid-receptor system in proteinuria and cardiac disorders. However, plasma aldosterone concentrations are not always increased in these conditions and the mechanisms of mineralocorticoid-receptor overactivation are difficult to determine. Using knockout mice, we identified a novel mechanism of Rac1-mediated podocyte impairment; Rac1 potentiates the activity of the mineralocorticoid receptor, thereby accelerating podocyte injury. We subsequently demonstrated that the Rac1-mineralocorticoid-receptor pathway contributes to ligand-independent mineralocorticoid-receptor activation in several animal models of kidney and cardiac injury. Hyperkalaemia is a major concern associated with the use of mineralocorticoid-receptor antagonists; however, agents that modulate the activity of the Rac1-mineralocorticoid-receptor pathway in target cells, such as cell-type-specific Rac inhibitors and selective mineralocorticoid-receptor modulators, could potentially be novel therapeutic candidates with high efficacy and a low risk of adverse effects in patients with renal and cardiac diseases.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Heart Diseases / metabolism*
  • Heart Diseases / pathology
  • Humans
  • Kidney Diseases / metabolism*
  • Kidney Diseases / pathology
  • Mice
  • Neuropeptides / metabolism*
  • Receptors, Mineralocorticoid / metabolism*
  • Signal Transduction / physiology*
  • rac GTP-Binding Proteins / metabolism*
  • rac1 GTP-Binding Protein / metabolism*

Substances

  • Neuropeptides
  • RAC1 protein, human
  • Rac1 protein, mouse
  • Receptors, Mineralocorticoid
  • rac GTP-Binding Proteins
  • rac1 GTP-Binding Protein