Epoxyeicosatrienoic acids, hypertension, and kidney injury.

Abstract

Kidney disease afflicts 33 million in the United States, and chronic kidney disease (CKD) accounts for >$60 billion in Medicare costs.1,2 Hypertension afflicts 75 million in the United States, and significant portions of those patients develop CKD and progress to end-stage renal disease.1–5 Interestingly, resistant hypertension which is defined as uncontrolled hypertension, despite 3 antihypertensive medication classes, increases the risk for cardiovascular diseases and end-stage renal disease.6 These recent findings in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) highlights the fact that current treatments only slow the loss of kidney function, or have no benefit at all.5,6 New therapeutic approaches are urgently needed. Development of drugs to increase a novel class of fatty acids, epoxyeicosatrienoic acids (EETs), represents a unique approach to treat hypertension and kidney disease. EETs are generated from the substrate arachidonic acid by cytochrome P450 (CYP) epoxygenase enzymes.7,8 There are 4 regioisomeric EETs formed: 5,6-EET; 8,9-EET; 11,12-EET; and 14,15-EET. These regioisomeric EETs are further metabolized to less active or inactive diols by the soluble epoxide hydrolase (sEH; Ephx2 ) enzyme. For clarity, EETs will be used as a general term and regioisomers mentioned when actions can be attributed to a specific regioisomeric EET. In the majority of circumstances, the primary EETs evaluated for cardiovascular and renal function have been 11,12-EET and 14,15-EET.7 Once formed, EETs act in an autocrine or paracrine manner to elicit biological responses. Vascular endothelial and renal epithelial cells are major sites for EET production.7,8 This localized EET generation aligns with the biological actions and contribution of EETs to cardiovascular and renal function. Prominent biological actions of EETs include their role as endothelial-derived hyperpolarizing factors and regulation of tubular sodium reabsorption by inhibiting epithelial …