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.

Fig. 1

Epoxyeicosatrienoic acid (EET) biological actions on (A) vascular smooth muscle, (B) renal cortical collecting duct cells, (C) organ apoptosis and fibrosis, and (D) inflammation. A: Endothelial-derived EETs activate vascular smooth muscle cell large conductance K⁺ channels (BK_Ca) resulting in hyperpolarization and vasodilation; B: EETs inhibit kiendy cortical collecting duct apical Na⁺ channels (ENaC) and basolateral K⁺ channels to decrease sodium reabsorption; C: EETs decrease endoplasmic reticulum (ER) stress, combat mitochondrial dysfunction, and inhibit transforming growth factor β1 (TGF-β1) to reduce apoptosis and decrease organ fibrosis; D: Tumor necrosis factor α (TNFα) activates a sequence of cell signaling events resulting in nuclear factor-κB (NF-κB) translocation to the nucleus to increase adhesion molecule levels to cause inflammatory cell infiltration. EETs act to prevent IKK phosphorylation and activation of NF-κB to decrease inflammation. Remodeling.

Fig. 2

Diagram depicting pathways of cytochrome P450 (CYP) arachidonic metabolism (Top) and changes in pathway that contribute to hypertension and kidney disease (Bottom). TOP: CYP2C and CYP2J enzymes generate epoxyeicosatrienoic acid (EETs). Soluble epoxide hydrolase (sEH) can hydrate EETs to form dihydroxyeicosatrienoic acids (DHETEs). BOTTOM: CYP2C, CYP2J, and EPHX2 polymorphisms result in decreased EET levels. Decreased EET levels result in endothelial dysfunction, inflammation, increased sodium reabsorption that contribute to hypertension and kidney disease.

Fig. 3

Development of epoxyeicosatrienoic acid (EET) analogs. TOP: Regioisomeric EET analogs for 8,9-EET, 11,12-EET, and 14,15-EET. MIDDLE: Folate conjugation of EET analogs results in kidney targeted EET analogs. BOTTOM: Modifications in EET analogs that result in orally active EET analogs.

Fig. 4

Diagram depicting epoxyeicosatrienoic acid (EET) analog actions that result in lowering blood pressure to combat hypertension. EET analogs act on vascular smooth muscle cells to cause vasodilation (left), inhibit epithelial sodium channels (ENaC) to increase sodium excretion (middle), and decrease activation of inflammatory cells (right).

Fig. 5

Diagram depicting epoxyeicosatrienoic acid (EET) analog actions that combat acute and chronic kidney diseases. EET analogs increase renal blood flow, decrease inflammation, and decrease glomerular permeability that decrease kidney fibrosis and apoptosis to slow or arrest the progression of acute and chronic kidney diseases.