Cell-specific mineralocorticoid receptors: future therapeutic targets for stroke?

Abstract

The mineralocorticoid receptor (MR), well known to be expressed in renal epithelial cells where it is important in fluid and electrolyte homeostasis, has aldosterone as one of its main agonists. Much research in the last 10–15 years indicates that MRs are also expressed outside of the kidney, including in the brain, vasculature and heart, where they contribute to the pathophysiology of disease (Dinh et al., 2012; Jaisser and Farman, 2016). Excess aldosterone is a cardiovascular risk factor, and MR antagonism is beneficial in the setting of cardiovascular disease (both clinically and experimentally), including in experimental stroke, whereby MR antagonism is beneficial in reducing both cerebral infarct size (Iwanami et al., 2007; Oyamada et al., 2008) and cerebral vascular remodeling (reviewed in Dinh et al., 2012) following cerebral ischemia. MR antagonism also reverses remodeling, both during aldosterone/mineralocorticoid excess and following cerebral ischemia. The advent of technology to generate mice which lack specific genes in specific cell types has allowed investigation into the contribution of MR in cell types such as vascular endothelial and myeloid cells to the pathophysiology of cerebrovascular disease and stroke (Frieler et al., 2011, 2012; Dinh et al., 2016). Endothelial cell MRs mediate cerebrovascular oxidative stress and brain inflammation in response to excess aldosterone (Dinh et al., 2016), and myeloid MR contribute to the ischemic damage, inflammation and neurological impairment following cerebral ischemia/reperfusion (Frieler et al., 2011, 2012). These and further investigations into the contribution of cell-specific MRs to cerebrovascular disease and stroke can help guide the future design of therapeutic strategies for stroke treatment.