Abstract P238: High Fat Diet-induced Obesity Disrupts Vascular Homeostasis in Both Kidney and Retina: Role of Epoxyeicosatrienoic Acids

Abstract

Obesity-induced vascular inflammation is considered an early and common pathological change for the development of microvascular complications including retinopathy and nephropathy. We have previously demonstrated that obesity down-regulated renal cytochrome P450 epoxygenase and decreased epoxyeicosatrienoic acids (EETs) levels in kidney as well as triggered retinal expression of the pro-inflammatory thioredoxin interacting protein (TXNIP) that coincided with vascular inflammation. The aim of this work is to examine the impact of obesity-induced reduction in EETs levels on TXNIP-inflammasome activation. Because EETs are quickly hydrolyzed by the soluble epoxide hydrolase (sEH) enzyme to inactive metabolites, we use sEH gene deleted mice (Ephx2 -/-) as a model with high EETs levels. WT and Ephx2 -/- were fed normal (14 % fat) or high fat diet (HFD, 60 % fat) for three months. HFD treatment down-regulated cyp2c44, the main epoxygenase for EETs production, and decreased EETs levels in kidney of obese mice and these changes were associated with podocyte loss and increased podocalyxin excretion as markers of glomerular injury. Although HFD treatment decreased EETs levels in Ephx2 -/- mice, it remained significantly higher than obese WT mice. HFD impaired endothelial function and induced TXNIP-inflammasome activation evident by increases in NOD-like receptor-3 (NLRP3) and interleukin-1β (IL-1β) in both retina and kidney. In parallel, HFD also increased leukostasis, retinal vascular permeability and development of acellular capillary, hall mark of ischemia in WT but not in TXNIP-/-. Restoring EETs levels in Ephx2 -/- mice improved endothelial function and was associated with decreased TXNIP-mediated inflammasome activation in the kidney of obese mice. Our data suggest that diet-induced obesity causes homeostatic imbalance by down-regulation of the anti-inflammatory epoxygenase/EETs levels and increasing the inflammatory TXNIP expression resulting in vascular injury in both retina and kidney.