Abstract 29: An Orally Active Epoxyeicosatrienoic Acid (eet) Analog Attenuates Kidney Injury in Hypertensive Dahl Salt Sensitive Rat by Reducing Oxidative Stress, Inflammation and Endoplasmic Reticulum Stress
Renal injury is associated with salt-sensitive hypertension. The Dahl salt-sensitive hypertensive rat (Dahl SS) is a model of salt-sensitive hypertension and the related kidney injury. The kidney injury in Dahl SS hypertension is associated with oxidative stress, inflammation and ER stress. We have recently developed orally active epoxyecosatrienoic acid (EET) analogs that provide organ protection in hypertension and other pathologies through multiple signaling pathways. We hypothesized that these EET analogs with their anti-inflammatory, anti-oxidant and anti-ER stress effects will protect the kidney in Dahl SS hypertension. Dahl SS rats received high salt diet and treated either with an EET analog (10 mg/kg/d) or vehicle (0.05% EtOH+0.1% PEG 400) in drinking water for 14 days. Blood pressure (SBP) was measured by tail-cuff plethysmography and urine, plasma and tissue samples were collected at the end of the treatment protocol. Urinary creatinine, albumin, nephrin, and renal tissue TBARS content were measured using ELISA or colorimetric assays. Renal expression of oxidative, inflammatory and ER stress marker genes were examined using RT-PCR. Histological analysis was done to assess renal injury. In Dahl SS rats, EET analog treatment did not affect the SBP compared to vehicle (183±6 vs. 185±12 mmHg). Interestingly, the EET analog treatment in Dahl SS reduced albumin-creatinine ratio (49±17 vs. 12±3) and nephrinuria (11±1 vs. 4±1 mg/d). EET analog treatment also reduced glomerular injury, intra-tubular cast formation and kidney fibrosis by 30-60% in Dahl SS rats compared to vehicle. In Dahl SS rats, EET analog treatment caused a 40% reduction in kidney TBARS content compared to vehicle. Moreover, the EET analog treatment in Dahl SS rats resulted 2-3 fold attenuation in the renal expression of oxidative (p47PHOX), inflammation (IL-6, TGF-β), and ER stress (CHOP, GADD34) genes. These data, demonstrate that a novel orally active EET analog provides kidney protection in Dahl SS hypertension by reducing oxidative stress, inflammation and ER stress, and this kidney protection was independent of blood pressure reduction.
- © 2012 by American Heart Association, Inc.