title: Mineralocorticoid receptor antagonism attenuates glomerular filtration barrier remodeling in the transgenic Ren2 rat.
abstract: 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.
authors.affiliation: Internal Medicine, University of Missouri-Columbia School of Medicine, Columbia, MO 65212, USA. whaleyconnella@health.missouri.edu
authors.forename: Adam
authors.initials: A
authors.lastname: Whaley-Connell
authors.forename: Javad
authors.initials: J
authors.lastname: Habibi
authors.forename: Yongzhong
authors.initials: Y
authors.lastname: Wei
authors.forename: Alex
authors.initials: A
authors.lastname: Gutweiler
authors.forename: Jessica
authors.initials: J
authors.lastname: Jellison
authors.forename: Charles E
authors.initials: CE
authors.lastname: Wiedmeyer
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Ferrario
authors.forename: James R
authors.initials: JR
authors.lastname: Sowers
mesh_terms: D000419:Albuminuria / Q000188:drug therapy / Q000503:physiopathology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007678:Kidney Glomerulus / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D000074624:NADPH Oxidase 1; D018384:Oxidative Stress / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D050199:Podocytes / Q000187:drug effects / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D017382:Reactive Oxygen Species / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D012083:Renin / Q000235:genetics*; D012084:Renin-Angiotensin System / Q000502:physiology*; D013148:Spironolactone / Q000494:pharmacology*
chemical_list: D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D000451:Mineralocorticoid Receptor Antagonists; D017382:Reactive Oxygen Species; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D051057:Proto-Oncogene Proteins c-akt; D012083:Renin