Mineralcorticoid Receptor (MR) Antagonism Attenuates Glomerular Filtration Barrier Remodeling in the Transgenic Ren2 Rat

Abstract

Renin‐angiotensin‐aldosterone system (RAAS) activation is associated with glomerular filtration barrier/podocyte injury & accompanying proteinuria. To explore potential MR mediated renal effects, Ren2 transgenic rats, which manifest increased tissue RAAS activity with elevated serum aldosterone levels, were used. Six week old Ren2 and Sprague‐Dawley rats were treated with a low dose of the MR antagonist spironolactone (SP)(0.24 mg/day) or vehicle for 21 days. Ren2 rats exhibited albuminuria, loss of podocyte‐specific proteins and podocyte foot‐process effacement on ultrastructural analysis, along with reduced expression of mediators of insulin metabolic signaling. Ren2 kidneys also manifested increased NADPH oxidase/ROS and redox‐sensitive Rho kinase activation in conjunction with enhanced renal tissue levels of MR, angiotensin type 1 receptor, angiotensin II and angiotensin‐(1‐12). SP treatment reduced albuminuria and tissue RAAS expression and improved podocyte structural and protein integrity along with improvements in insulin metabolic signaling. MR blockade directly provides protection in this model of renal RAAS activation, in part, through reductions in redox‐sensitive ROK impairment of insulin metabolic signaling and glomerular remodeling.Supported by NIH R01 HL73101‐01A1 (JRS) & HL‐51952 (CMF), VA Merit (JRS), VA VISN 15 (AWC), & Missouri Kidney Program (AWC).

Cardiometabolic Development Mechanisms Obesity Syndrome

“…Признано, что висцеральное/абдоминальное ожирение играет более значимую роль в развитии патологии по сравнению с периферической адипозной тканью в секреции свободных жирных кислот (СЖК) и адипоцитокинов [13]. Дисфункция адипоцитов при ожирении вовлечена в развитие ИР, Д2Т, АС, АГ, стеатоза печени и других метаболических нарушений, характерных для КМС [7,8,14].…”