Regulation of Cytochrome P-450 4A Activity by Peroxisome Proliferator-Activated Receptors in the Rat Kidney

Ishizuka, Tsuneo; Ito, Osamu; Tan, Lian; Ogawa, Susumu; Kohzuki, Masahiro; Omata, Ken; Takeuchi, Kazuhisa; Ito, Sadayoshi

doi:10.1291/hypres.26.929

Cited by 39 publications

(27 citation statements)

References 45 publications

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“…4). These results are consistent with those of studies showing that clofibrate induces renal CYP4A expression and that its induction is correlated with increased 20-HETE production in the rat kidney (Cummings et al, 1999;Ishizuka et al, 2003).…”

Section: Discussionsupporting

confidence: 92%

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Induction of Renal 20-Hydroxyeicosatetraenoic Acid by Clofibrate Attenuates High-Fat Diet-Induced Hypertension in Rats

Zhou

Huang

Chang

et al. 2005

J Pharmacol Exp Ther

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This study compared renal hemodynamics, the expression of CYP4A isoforms [the enzymes for 20-hydroxyeicosatetraenoic acid (20-HETE) production], and tubular sodium transporters in male rats fed a high-fat (HF) or control diet for 10 weeks. We also studied the effect of treatment with clofibrate, a CYP4A inducer, on sodium retention and renal function and on CYP4A expression in HF rats. HF rats had higher blood pressure (BP), renal plasma flow, and glomerular filtration rate (GFR), but no significant change in renal vascular resistance. Reverse transcription-polymerase chain reaction analysis showed that CYP4A1 and CYP4A8 expression was significantly decreased in the renal cortex of HF rats. Western blot analysis showed up-regulation of expression of the ␣-subunit of the epithelial sodium channel (␣-ENaC), the ␤-subunit of the epithelial sodium channel (␤-ENaC), sodium/hydrogen exchanger (NHE)-3, and the renal outer medulla K ϩ channel (ROMK) in HF rats, whereas expression of the ␥-subunit of the epithelial sodium channel and the ␣1-subunit of Na ϩ -K ϩ -ATPase remained unchanged. Thus, HF treatment caused the reduction of renal CYP4A1 and CYP4A8 expression, whereas the increases in ␣-ENaC, ␤-ENaC, NHE-3, and ROMK expression in renal tubules may have contributed sodium retention and hypertension in HF rats. Furthermore, clofibrate treatment (240 mg/kg/day) caused the decrease of BP and GFR and the attenuation of cumulative sodium balance in HF rats. The attenuation of sodium retention by clofibrate treatment is linked to decreased expression of NHE-3 in renal cortex. Clofibrate induction of CYP4A expression occurred in proximal tubules and in the thick ascending limb of the loop of Henle but not in renal microvessels. This induction correlated with the expression of peroxisome proliferator-activated receptor (PPAR␣) in renal tubules. Therefore, these results suggest that the effects of clofibrate on sodium retention and blood pressure regulation in HF rats may be due to the induction of renal tubular 20-HETE production through the PPAR␣ pathway.Findings from the 1999 -2000 National Health and Nutrition Examination Survey showed that 59 million adults or 31% of those in the United States are obese. Obesity is an important factor in essential hypertension (Hall, 2003). We have chosen to study rats fed a HF diet because this model mimics the effects of human HF-food consumption. These rats develop characteristic features of human obesity-induced hypertension such as increased sodium balance, renal tubular reabsorption, and glomerular filtration rate (Dobrian et al., 2000;Hall, 2003).20-Hydroxyeicosatetraenoic acid (20-HETE) is a major metabolite of arachidonic acid in the rat kidneys; its synthesis and actions have been localized primarily to the microcirculation and renal tubules (Roman, 2002). 20-HETE synthesis is catalyzed primarily by CYP4A isoforms (Roman, 2002 ABBREVIATIONS: HF, high fat; HETE, 20-hydroxyeicosatetraenoic acid; TALH, thick ascending limb of the loop of Henle; ROMK, renal outer medulla K...

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Section: Discussionsupporting

confidence: 92%

“…7). Similar tissue distribution of PPAR␣ expression in the renal tubules but not in preglomerular arterioles has been reported (Ishizuka et al, 2003). More interestingly, the up-regulation of CYP4A in response to clofibrate treatment of HF rats is associated with reduced sodium retention and blood pressure (Fig.…”

Section: Discussionsupporting

confidence: 78%

Induction of Renal 20-Hydroxyeicosatetraenoic Acid by Clofibrate Attenuates High-Fat Diet-Induced Hypertension in Rats

Zhou

Huang

Chang

et al. 2005

J Pharmacol Exp Ther

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“…The lack of effect of FF on Cyp4a protein levels in the vasculature of the kidney may be caused by lack of peroxisome-activated receptor-␣ receptors on renal vessels as previously reported in the rat. 17 Studies in the Dahl S rat have clearly indicated a role for altered outer medullary 20-HETE production in the development of salt-sensitive hypertension in this model. 4,5 Similar observations between urinary levels of 20-HETE and sodium excretion have recently been reported in salt-sensitive versus salt-resistant patients.…”

Section: Discussionmentioning

confidence: 93%

Fenofibrate Prevents the Development of Angiotensin II–Dependent Hypertension in Mice

et al. 2005

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Abstract-Previous studies have indicated that the production of 20-hydroxyecisatatraenoic acid (20-HETE) is similar in the liver of C57/B6 mice and rats, but the renal production of 20-HETE is very low in this strain of mice. The present study examined the effects of induction of the renal production of 20-HETE with fenofibrate (FF) on the development of angiotensin II (Ang II)-dependent hypertension in C57BL/6J mice. The mice were divided into 4 groups and treated with vehicle (control), FF (90 mg/kg per day, IP), Ang II (1000 ng/kg per minute, SC), and Ang II plus FF. Mean arterial blood pressure (MAP) averaged 109Ϯ4 and 106Ϯ2 mm Hg in control and FF-treated mice (nϭ7). MAP was significantly increased in the Ang II-treated mice to 144Ϯ4 mm Hg (nϭ7). However, FF treatment prevented the development of Ang II-dependent hypertension, with MAP averaging 115Ϯ5 mm Hg in mice treated with both Ang II plus FF (nϭ7). Renal production of 20-HETE was very low in control (nϭ7) and Ang II-treated (nϭ7) mice and was increased by Ͼ2-fold in FF-treated (nϭ7) and Ang II plus FF-treated (nϭ7) mice. The levels of Cyp4A proteins were markedly increased in the kidneys of mice treated with FF and Ang II plus FF but not in the renal vasculature. These results suggest that upregulation of the production of 20-HETE in renal tubules may contribute to the blood pressure-lowering effects of FF treatment in Ang II-dependent hypertension in C57BL/6J mice. 1 Of these metabolites, 20-hydroxyecisatatraenoic acid (20-HETE) has been reported to inhibit sodium transport and promote natriuresis. 2,3 Studies in Dahl salt-sensitive (Dahl S) rats indicate that production of 20-HETE in the outer medulla is reduced and that this defect contributes to the development of salt-sensitive hypertension in this model. 4,5 Induction of the renal expression of Cyp4a enzymes in the kidney using fibrate compounds has been reported to lower blood pressure in spontaneously hypertensive rats (SHR) and stroke-prone SHR and Dahl S rats. 6,7 The reduction of blood pressure with clofibrate in Dahl S rats was also associated with the normalization of the pressurenatruretic response in this model. 8 In mice, the expression of Cyp4A proteins and renal 20-HETE production is reduced during the development of deoxycorticosterone acetate-salt hypertension. 9 Induction of the renal production of 20-HETE with bezafibrate lowered the blood pressure and improved renal hemodynamics in this model. 10 These studies suggest that a deficiency in the renal production of 20-HETE may promote the development of hypertension. More recently, we have reported that the renal production of 20-HETE is also very low in the kidney of C57BL/6J mice, 11 indicating that they may be a good model to determine the role of CYP metabolites of AA in the regulation of renal function and blood pressure. Thus, the present study examined the effects of induction of the renal production of 20-HETE with FF on the development of Ang II-dependent hypertension in C57BL/6J mice.

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“…Most investigators have reported that PIO does not affect P-450 expression and activity in the kidney. 31,32 In vitro experiments showed that PIO induces CYP3A4 and CYP2B6 expression in primary human hepatocytes. However, PIO also has the potential to inhibit CYP2C8 activity.…”

Section: · Dmentioning

confidence: 99%

Augmentation of Myocardial Production of 15-Epi-Lipoxin-A ₄ by Pioglitazone and Atorvastatin in the Rat

et al. 2006

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Background-Both statins and thiazolidinediones have antiinflammatory properties. However, the exact mechanisms underlying these effects are unknown. We investigated whether atorvastatin (ATV) and pioglitazone (PIO) increase the myocardial content of lipoxin-A 4 and 15(R)-epi-lipoxin-A 4 (15-epi-LXA 4 ), both arachidonic acid products with strong antiinflammatory properties. Methods and Results-In experiment 1, rats received 3-day pretreatment with water; PIO 2, 5, or 10 mg · kg Ϫ1 · d Ϫ1 ; ATV 2, 5, or 10 mg · kg Ϫ1 · d

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Regulation of Cytochrome P-450 4A Activity by Peroxisome Proliferator-Activated Receptors in the Rat Kidney

Cited by 39 publications

References 45 publications

Induction of Renal 20-Hydroxyeicosatetraenoic Acid by Clofibrate Attenuates High-Fat Diet-Induced Hypertension in Rats

Induction of Renal 20-Hydroxyeicosatetraenoic Acid by Clofibrate Attenuates High-Fat Diet-Induced Hypertension in Rats

Fenofibrate Prevents the Development of Angiotensin II–Dependent Hypertension in Mice

Augmentation of Myocardial Production of 15-Epi-Lipoxin-A ₄ by Pioglitazone and Atorvastatin in the Rat

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Regulation of Cytochrome P-450 4A Activity by Peroxisome Proliferator-Activated Receptors in the Rat Kidney

Cited by 39 publications

References 45 publications

Induction of Renal 20-Hydroxyeicosatetraenoic Acid by Clofibrate Attenuates High-Fat Diet-Induced Hypertension in Rats

Induction of Renal 20-Hydroxyeicosatetraenoic Acid by Clofibrate Attenuates High-Fat Diet-Induced Hypertension in Rats

Fenofibrate Prevents the Development of Angiotensin II–Dependent Hypertension in Mice

Augmentation of Myocardial Production of 15-Epi-Lipoxin-A 4 by Pioglitazone and Atorvastatin in the Rat

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Product

Resources

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Augmentation of Myocardial Production of 15-Epi-Lipoxin-A ₄ by Pioglitazone and Atorvastatin in the Rat