Abstract
Aldosterone modulates the activity of both epithelial (specifically renal) and non-epithelial cells. Binding to the mineralocorticoid receptor (MR), activates two pathways: the classical genomic and the rapidly activated non-genomic that is substantially modulated by the level of striatin. We hypothesized that disruption of MR’s non-genomic pathway would alter aldosterone-induced cardiovascular/renal damage. To test this hypothesis, wild type (WT) and striatin heterozygous knockout (Strn+/−) littermate male mice were fed a liberal sodium (1.6% Na+) diet and randomized to either protocol one: 3 weeks of treatment with either vehicle or aldosterone plus/minus MR antagonists, eplerenone or esaxerenone or protocol two: 2 weeks of treatment with either vehicle or L-NAME/AngII plus/minus MR antagonists, spironolactone or esaxerenone. Compared to the WT mice, basally, the Strn+/− mice had greater (~26%) estimated renal glomeruli volume and reduced non-genomic second messenger signaling (pAkt/Akt ratio) in kidney tissue. In response to active treatment, the striatin-associated-cardiovascular/renal damage was limited to volume effects induced by aldosterone infusion: significantly increased blood pressure (BP) and albuminuria. In contrast, with aldosterone or L-NAME/AngII treatment, striatin deficiency did not modify aldosterone-mediated damage: in the heart and kidney, macrophage infiltration, and increases in aldosterone-induced biomarkers of injury. All changes were near-normalized following MR blockade with spironolactone or esaxerenone, except increased BP in the L-NAME/AngII model. In conclusion, the loss of striatin amplified aldosterone-induced damage suggesting that aldosterone’s non-genomic pathway is protective but only related to effects likely mediated via epithelial, but not non-epithelial cells.
Highlights
During the past two decades, a substantial expansion has occurred in understanding aldosterone’s mechanism of action, in two areas – cells targeted and pathways used
We used the Strn+/– mouse since we have documented that striatin is a critical intermediary required to activate mineralocorticoid receptor (MR)’s nongenomic pathway
Striatin deficiency did not affect indices related to inflammation in the heart or the kidney in the aldosterone infusion model
Summary
During the past two decades, a substantial expansion has occurred in understanding aldosterone’s mechanism of action, in two areas – cells targeted and pathways used. It is well known that activation of the aldosterone/MR pathway, in the presence of a liberal sodium (1.6% Na+), diet, is a risk factor for a variety of cardiovascular/renal diseases and that MR antagonists (MRA) can ameliorate these adverse effects (Takeda et al 2000, Martinez et al 2002, Rocha et al 2002, Endemann et al 2004, Jain et al 2009) It is unclear whether the aldosteroneinduced cardiovascular and renal damage is being mediated by its actions on epithelial (renal, volume) and/or non-epithelial cell types. Among the established experimental models of cardiovascular and renal damage, two involving MR activation are illustrative of contrasting approaches – exogenously administered aldosterone and NG-nitro-Larginine methyl ester (L-NAME) induced deficiency of nitric oxide/angiotensin II (AngII) (Oestreicher et al 2003) Both require a liberal sodium diet (1.6% Na+) to produce the damage. To assess the specificity of our findings were related to activation of the MR, we used two MRA’s – eplerenone (steroid based) and esaxerenone (non-steroid based)
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