Epoxide hydrolase and epoxygenase metabolites as therapeutic targets for renal diseases.

Renal epoxygenase metabolites are involved in blood flow regulation and long-term blood pressure control. One feature of renal and cardiovascular diseases is the inability of the kidney to properly increase epoxyeicosatrienoic acid (EET) levels. Others (Busse R, Edwards G, Félétou M, Fleming I, Vanhoutte PM, and Weston AH. Trends Phamacol Sci 23: 374-380, 2002; Campbell WB, Gebremedhin D, Pratt PF, and Harder DR. Circ Res 78: 415-423, 1996; Capdevila JH and Falck JR. Biochem Biophys Res Commun 285: 571-576, 2001; Roman RJ. Physiol Rev 82: 131-185, 2002; Zeldin DC. J Biol Chem 276: 36059-36062, 2001) and we (Imig JD, Falck JR, Wei S, and Capdevila JH. J Vasc Res 38: 247-255, 2001; Imig JD, Zhao X, Capdevila JH, Morisseau C, and Hammock BD. Hypertension 39: 690-694, 2002; Zhao X, Pollock DM, Inscho EW, Zeldin DC, and Imig JD. Hypertension 41: 709-714, 2003; Zhao X, Pollock DM, Zeldin DC, and Imig JD. Hypertension 42: 775-780, 2003) have provided compelling evidence that cytochrome P-450-derived EETs have antihypertensive properties and are endothelially derived hyperpolarizing factors (EDHFs) in the kidney. EETs also possess anti-inflammatory actions that could protect the kidney vasculature from injury during renal and cardiovascular diseases. A tactic that has been used to increase EET levels has been inhibition of the soluble epoxide hydrolase enzyme. Epoxide hydrolase inhibitors have been demonstrated to be antihypertensive and renal protective. Thus the renal and cardiovascular protective actions of increasing epoxygenase levels could be translated to therapies for preventing end-organ damage.