Orally active epoxyeicosatrienoic acid analogs in hypertension and renal injury

Abstract

Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites synthesized by cytochrome P450 epoxygenases. Biological activities for EETs include vasodilation, decreasing inflammation, opposing apoptosis, and inhibiting renal sodium reabsorption. These actions are beneficial in lowering blood pressure and slowing kidney disease progression. Furthermore, evidence in human and experimental animal studies have found that decreased EET levels contribute to hypertension and kidney diseases. Consequently, EET mimics/analogs have been developed as a potential therapeutic for hypertension and acute and chronic kidney diseases. Their development has resulted in EET analogs that are orally active with favorable pharmacological profiles. Analogs for 8,9-EET, 11,12-EET, and 14,15-EET have been tested in several hypertension and kidney disease animal models. More recently, kidney targeted EET analogs have been synthesized and tested against drug-induced nephrotoxicity. Experimental evidence has demonstrated compelling therapeutic potential for EET analogs to oppose cardiovascular and kidney diseases. These EET analogs lower blood pressure, decrease kidney inflammation, improve vascular endothelial function, and decrease kidney fibrosis and apoptosis. Overall, these preclinical studies support the likelihood that EET analogs will advance to clinical trials for hypertension and associated comorbidities or acute and chronic kidney diseases.

Keywords: Chronic kidney disease; Cytochrome P450; Endothelium; Epoxyeicosatrienoic acids; Hypertension; Inflammation; Sodium transport.