Renal epoxyeicosatrienoic acid synthesis during pregnancy.

Epoxyeicosatrienoic acids (EETs), which belong to cytochrome P-450 (CYP)-derived eicosanoids, have been implicated to vasodilate renal arterioles, inhibit sodium transport in the nephron, and regulate blood pressure in several animal models. Because pregnancy is associated with changes of blood pressure, the aim of this study was to examine whether renal EET synthesis is altered and whether EETs are involved in blood pressure regulation during pregnancy in rats. Renal microsomal epoxygenase activity increased by 47, 97, and 63% on days 6, 12, and 19 of gestation, respectively. The elevation of epoxygenase activity during pregnancy was associated with an increase in CYP2C11, CYP2C23, and CYP2J2 protein expression on days 6, 12, and 19 of gestation. Moreover, immunohistochemical analysis showed that renal tubular CYP2C11, CYP2C23, and CYP2J2 expression was significantly increased in pregnant rats on days 6, 12, and 19 of gestation. Administration of 6-(2-propargyloxyphenyl)hexanoic acid (PPOH), a selective epoxygenase inhibitor, caused a dose-dependent inhibition of microsomal expoxygenase activity without a significant effect on omega-hydroxylase activity in female rats. Interestingly, administration of PPOH (20 mg.kg(-1).day(-1) for 4 days starting on day 15 of pregnancy) increased blood pressure by 21 mmHg and caused a significant decrease in the body weight of fetal pups (1.3 +/- 0.08 g in control vs. 1.1 +/- 0.06 g in PPOH). Moreover, PPOH treatment significantly decreased renal microsomal epoxygenase activity and the expression of CYP2C11, CYP2C23, and CYP2J in pregnant rats. This study demonstrates that EET synthesis in the kidney is elevated during pregnancy, and CYP2C11, 2C23, and CYP2J2 are responsible for the change of renal EET synthesis. The inhibition results demonstrate that the downregulation of renal epoxygenase activity by PPOH causes hypertension in pregnant rats. This study suggests that EETs may contribute to the control of blood pressure during pregnancy.

[1]  K. Burns,et al.  NO inhibits Na+-K+-2Cl- cotransport via a cytochrome P-450-dependent pathway in renal epithelial cells (MMDD1). , 2003, American journal of physiology. Renal physiology.

[2]  Lianwei Jiang,et al.  Structure-function relationships of AE2 regulation by Ca(i)(2+)-sensitive stimulators NH(4+) and hypertonicity. , 2003, American journal of physiology. Cell physiology.

[3]  J. Granger,et al.  Vascular mechanisms of increased arterial pressure in preeclampsia: lessons from animal models. , 2002, American journal of physiology. Regulatory, integrative and comparative physiology.

[4]  B. Hammock,et al.  Soluble Epoxide Hydrolase Inhibition Lowers Arterial Blood Pressure in Angiotensin II Hypertension , 2002, Hypertension.

[5]  R. Roman,et al.  P-450 metabolites of arachidonic acid in the control of cardiovascular function. , 2002, Physiological reviews.

[6]  J. Falck,et al.  Epoxygenase Metabolites Contribute to Nitric Oxide-Independent Afferent Arteriolar Vasodilation in Response to Bradykinin , 2001, Journal of Vascular Research.

[7]  F. Gonzalez,et al.  Targeted Disruption of Soluble Epoxide Hydrolase Reveals a Role in Blood Pressure Regulation* , 2000, The Journal of Biological Chemistry.

[8]  E. Brand-Schieber,et al.  Selective inhibition of arachidonic acid epoxidation in vivo. , 2000, Journal of physiology and pharmacology : an official journal of the Polish Physiological Society.

[9]  J. Imig.  Eicosanoid regulation of the renal vasculature. , 2000, American journal of physiology. Renal physiology.

[10]  B D Hammock,et al.  Soluble Epoxide Hydrolase Regulates Hydrolysis of Vasoactive Epoxyeicosatrienoic Acids , 2000, Circulation research.

[11]  I. Fleming,et al.  Cytochrome P450 2C is an EDHF synthase in coronary arteries. , 2000, Trends in cardiovascular medicine.

[12]  D. Kroetz,et al.  Increased CYP2J expression and epoxyeicosatrienoic acid formation in spontaneously hypertensive rat kidney. , 2000, Molecular pharmacology.

[13]  V. Holla,et al.  The kidney cytochrome P-450 2C23 arachidonic acid epoxygenase is upregulated during dietary salt loading. , 1999, The Journal of clinical investigation.

[14]  J. Mcgiff,et al.  20-HETE and the kidney: resolution of old problems and new beginnings. , 1999, American journal of physiology. Regulatory, integrative and comparative physiology.

[15]  K. Tomer,et al.  Molecular Cloning, Enzymatic Characterization, Developmental Expression, and Cellular Localization of a Mouse Cytochrome P450 Highly Expressed in Kidney* , 1999, The Journal of Biological Chemistry.

[16]  J. Granger,et al.  Differential expression of renal nitric oxide synthase isoforms during pregnancy in rats. , 1999, Hypertension.

[17]  J. Granger,et al.  Enhanced vascular reactivity during inhibition of nitric oxide synthesis in pregnant rats. , 1998, Hypertension.

[18]  J. Falck,et al.  Cytochrome P450-derived arachidonic acid metabolism in the rat kidney: characterization of selective inhibitors. , 1998, The Journal of pharmacology and experimental therapeutics.

[19]  L. Navar,et al.  Actions of epoxygenase metabolites on the preglomerular vasculature. , 1996, Journal of the American Society of Nephrology : JASN.

[20]  K. Tomer,et al.  Molecular Cloning and Expression of CYP2J2, a Human Cytochrome P450 Arachidonic Acid Epoxygenase Highly Expressed in Heart (*) , 1996, The Journal of Biological Chemistry.

[21]  H. Jacobson,et al.  5,6-EET inhibits ion transport in collecting duct by stimulating endogenous prostaglandin synthesis. , 1995, The American journal of physiology.

[22]  E. Oliw.  Oxygenation of polyunsaturated fatty acids by cytochrome P450 monooxygenases. , 1994, Progress in lipid research.

[23]  H. Jacobson,et al.  Molecular cloning, expression, and enzymatic characterization of the rat kidney cytochrome P-450 arachidonic acid epoxygenase. , 1993, The Journal of biological chemistry.

[24]  A. Katz,et al.  Intracellular signaling in the regulation of renal Na-K-ATPase. II. Role of eicosanoids. , 1993, The Journal of clinical investigation.

[25]  H. Jacobson,et al.  Cytochrome P-450 arachidonic acid epoxygenase. Regulatory control of the renal epoxygenase by dietary salt loading. , 1992, The Journal of biological chemistry.

[26]  Gerhard Giebisch,et al.  The Kidney: Physiology and Pathophysiology , 1992 .

[27]  J. Douglas,et al.  An epoxygenase metabolite of arachidonic acid mediates angiotensin II-induced rises in cytosolic calcium in rabbit proximal tubule epithelial cells. , 1991, The Journal of clinical investigation.