Recent evidence suggests that
mineralocorticoid receptor (MR) antagonism has beneficial effects on tissue oxidative stress and
insulin metabolic signaling as well as reducing
proteinuria. However, the mechanisms by which MR antagonism corrects both renin-angiotensin-aldosterone system (RAAS) impairments in renal
insulin metabolic signaling and filtration barrier/podocyte injury remain unknown. To explore this potential beneficial interactive effect of MR antagonism we used young transgenic (mRen2)27 (Ren2) rats with increased tissue RAAS activity and elevated serum
aldosterone levels. Ren2 and age-matched Sprague-Dawley (SD) control rats (age 6-7 wk) were implanted with a low dose of the MR antagonist
spironolactone (0.24 mg/day) or vehicle, both delivered over 21 days.
Albuminuria, podocyte-specific
proteins (synaptopodin,
nephrin, and
podocin), and ultrastructural analysis of the glomerular filtration barrier were measured in relation to RAAS activation of reduced
nicotinamide adenine dinucleotide phosphate (
NADPH) oxidase,
reactive oxygen species (ROS), and the redox-sensitive
Rho kinase (ROK).
Insulin metabolic signaling was determined via measurement of
insulin receptor substrate-1 (IRS-1) phosphorylation, IRS-1
ubiquitin/proteasomal degradation, and phosphorylation of Akt. Ren2 rats exhibited
albuminuria, loss of podocyte-specific
proteins, and podocyte foot process effacement contemporaneous with reduced renal IRS-1 and
protein kinase B/Akt phosphorylation compared with SD control rats (each P < 0.05). Ren2 kidneys also manifested increased
NADPH oxidase/ROS/ROK in conjunction with enhanced renal tissue levels of
angiotensin II (ANG II), ANG-(1-12), and
angiotensin type 1 receptor. Low-dose
spironolactone treatment reduced
albuminuria and tissue RAAS activity and improved podocyte structural and
protein integrity with improvements in IRS-1/Akt phosphorylation. Thus, in this model of RAAS activation, MR antagonism attenuates glomerular/podocyte remodeling and
albuminuria, in part through reductions in redox-mediated impairment of
insulin metabolic signaling.