Linking an insect enzyme to hypertension: angiotensin II–epoxide hydrolase interactions  Ding Ai, John Y.-J. Shyy, Yi Zhu  Kidney International  Volume 77, Issue 2, Pages 88-92 (January 2010) DOI: 10.1038/ki.2009.349 Copyright © 2010 International Society of Nephrology Terms and Conditions

Figure 1 Arachidonic acid (AA) is generated by the catalysis of phospholipase A2 (PLA2) from membrane phospholipids. AA is converted to many metabolic products. Although epoxyeicosatrienoic acids (EETs) are formed by cytochrome P450, cyclooxygenases (COXs) convert AA to prostanoids, and lipoxygenases (LOXs) generate leukotrienes and prostaglandins. CYP2C and CYP2J are the two major human CYP isoforms that convert AA to 5,6-, 8,9-, 11,12-, or 14,15-EET. Soluble epoxide hydrolase (sEH) converts the EETs to their corresponding less-active diols, dihydroxyeicosatrienoic acids. CYP, cytochrome P450 epoxgenases. Kidney International 2010 77, 88-92DOI: (10.1038/ki.2009.349) Copyright © 2010 International Society of Nephrology Terms and Conditions

Figure 2 Overview of the signal transduction pathways stimulated by angiotensin II (Ang II) in the cardiovascular system. Ang II binds to angiotensin type 1 receptor (AT1) to activate several signaling pathways, with consequent upregulation of the downstream transcriptional factors, including nuclear factor (NF)-κB, activating protein 1 (AP-1), nuclear factor of activated T-cell (NFAT), and signal transducers and activators of transcription (STATs). Each transcriptional factor governs its targeting genes as listed. sEH is transcriptionally upregulated by the AP-1 pathway. All these genes contribute to the effects of Ang II, including vasoconstriction, vascular inflammation, cell proliferation, myocardial hypertrophy, fibrosis, and renal damage. Because sEH inhibitors can ameliorate most effects induced by Ang II, sEH has an important role in the function of Ang II in the cardiovascular system. sEH, soluble epoxide hydrolase. Kidney International 2010 77, 88-92DOI: (10.1038/ki.2009.349) Copyright © 2010 International Society of Nephrology Terms and Conditions

Figure 3 The binding of Ang II to its receptor AT1 activates AP-1 and increases the binding of AP-1 to the cognate cis-element in the sEH promoter to enhance the expression of sEH. The increased sEH promotes the hydrolization of more EETs into dihydroxyeicosatrienoic acids (DHETs). With decreased EETs released from endothelial cells, the paracrine effect of EETs on vascular smooth muscle cell hyperpolarization is attenuated, which increases blood pressure. Ang II, angiotensin II; AP-1, activating protein 1; AT1, angiotensin type 1 receptor; EETs, epoxyeicosatrienoic acids; sEH, soluble epoxide hydrolase. Kidney International 2010 77, 88-92DOI: (10.1038/ki.2009.349) Copyright © 2010 International Society of Nephrology Terms and Conditions