Abstract P266: Western Diet Impairs Small Vessel Relaxation and Initiates Kidney Endothelial Stiffening, Fibrosis and Tubulointerstitial Fibrosis Through the Endothelial Mineralocorticoidreceptor

Abstract

Obesity enhances mineralocorticoid receptor (MR) activation, development of vascular stiffness and end organ injury. In this context, western diet (WD) activation of the endothelial mineralocorticoid receptor (ECMR) contributes to endothelial cell stiffening and promotes maladaptive inflammatory responses and fibrosis in cardiovascular tissue of female mice. However, the role of ECMR on kidney endothelial stiffening, inflammation and fibrosis remains unknown. We hypothesized that deletion of the ECMR would prevent WD-induced increases in endothelial cell stiffness, reductions in bioavailable nitric oxide (NO), increased perivascular and tubulointerstitial inflammation oxidant stress, and fibrosis in females. Four-week-old female ECMR knockout and wild-type mice were fed either a mouse chow or a WD high in saturated fat and refined carbohydrates for 16 weeks. Without blood pressure changes between groups, WD-feeding increased body weight and fat mass as well as indices of vascular stiffness (pulse wave velocity and kidney endothelial cell stiffness) and impaired endothelial-dependent vasodilatation. The WD-induced kidney endothelial cell stiffness was associated with attenuated endothelial NO synthase activation, increased oxidative stress, along with pro-inflammatory immune responses, alterations in extracellular matrix degradation pathways and tubulointerstitial fibrosis. ECMR deletion prevented these abnormalities through improvements in endothelial NO synthase and reductions in macrophage polarization, LARP6, TG2 and MMP2. Our data support that activation of ECMR contributes to endothelial dysfunction, increased permeability and stiffening in the kidney which, in turn, promotes macrophage infiltration, M1 polarization, inflammation and oxidative stress, resulting in alterations in matrix degradation that promote tubulointerstitial fibrosis in females consuming a WD.