A Peroxisome Proliferator-Activated Receptor-α Activator Induces Renal CYP2C23 Activity and Protects from Angiotensin II-Induced Renal Injury

Müller, Dominik N.; Theuer, Juergen; Shagdarsuren, Erdenechimeg; Kaergel, Eva; Honeck, Horst; Park, Joon-Keun; Marković, Marija; Barbosa-Sicard, Eduardo; Dechend, Ralf; Wellner, Maren; Kirsch, Torsten; Fiebeler, Anette; Rothe, Michael; Haller, Hermann; Luft, Friedrich C.; Schunck, Wolf‐Hagen

doi:10.1016/s0002-9440(10)63142-2

Cited by 97 publications

(101 citation statements)

References 45 publications

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“…However, the further analysis in intact proximal tubules revealed that Ang II failed to activate ERK in the presence of arachidonic acid or 5,6-EET, supporting the negative effect of arachidonic acid metabolites on the ERK pathway (Li, Y and Seki G, unpublished observation). Moreover, the negative effect of EET on ERK activation is consistent with a protective role of EET in Ang II-induced renal injury [71]. In this model, AT 1 mediates both stimulatory and inhibitory effects of Ang II.…”

Section: Roles Of Arachidonic Acid Metabolites In Ang II Actionssupporting

confidence: 80%

“…It is tempting to speculate, however, that renal proximal tubules may have to develop the unique mechanism to attenuate excessive actions of Ang II. Indeed, in situ proximal tubular fluid is reported to contain markedly high concentrations of Ang II [44], and uncontrolled Ang II actions may result in unwarranted sequences such as cell hypertrophy or cell damage [14,71].…”

Section: Roles Of Arachidonic Acid Metabolites In Ang II Actionsmentioning

confidence: 99%

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Roles of MEK/ERK Pathway in Vascular and Renal Tubular Actions of Angiotensin II

Seki¹,

Yamada²,

Li³

et al. 2009

VDP

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Chronic kidney disease (CKD) is now widely recognized as a significant risk factor for cardiovascular disease (CVD). Chronic angiotensin II (Ang II) stimulation facilitates tissue hyperplasia, hypertrophy, and inflammation, and the current medical strategy for CKD is primarily based on the suppression of rein-angiotensin system. Since Ang II induces hypertension through both vasoconstriction and sodium retention, the understanding of vascular and renal actions of Ang II is essential for the better management of CKD and CVD. Ang II is coupled to a variety of intracellular signaling pathways depending on cell types, and Ang II type 1 receptor (AT 1 ) is thought to be responsible for most, if not all, of the cardiovascular effects of Ang II. Recent studies have suggested that the MEK/ERK pathway plays an important role in Ang II-mediated vascular smooth muscle contraction, where cytosolic phospholipase A 2 (cPLA 2 )/P450 pathway has a positive feedback effect. Interestingly, the MEK/ERK pathway has been also shown to mediate the stimulatory effect of Ang II on renal proximal transport. However, the cPLA 2 /P450 pathway has a negative feedback effect on the Ang II-mediated ERK activation in renal proximal tubules. Thus, arachidonic acid metabolites seem to play quite contrasting roles in the Ang IImediated ERK activation in vascular and renal tissues. This article will be focused on the roles of MEK/ERK pathway in vascular and renal tubular actions of Ang II.

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Section: Roles Of Arachidonic Acid Metabolites In Ang II Actionssupporting

confidence: 80%

Section: Roles Of Arachidonic Acid Metabolites In Ang II Actionsmentioning

confidence: 99%

Roles of MEK/ERK Pathway in Vascular and Renal Tubular Actions of Angiotensin II

Seki¹,

Yamada²,

Li³

et al. 2009

VDP

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“…PPAR-␣ activation has been shown to induce renal CYP2C23 activity under pathological and nonpathological conditions. 32,33 Contrary to the effects of A-192621 treatment on CYP4A expression in rats on high salt, chronic ET B blockade did not change CYP2C23 protein expression. Furthermore, clofibrate administration did not influence CYP2C23 expression in A-192621-treated rats on a high-salt diet.…”

Section: Discussionmentioning

confidence: 87%

Peroxisome Proliferator-Activated Receptor-α Activation Reduces Salt-Dependent Hypertension During Chronic Endothelin B Receptor Blockade

et al. 2005

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Abstract-Endothelin B (ET B ) receptor stimulation inhibits sodium transport in a similar fashion as 20-HETE. Clofibrate, a peroxisome proliferator-activated receptor-␣ (PPAR-␣) agonist, increases protein expression of cytochrome P450 4A (CYP4A), which is responsible for 20-HETE synthesis in the kidney. Experiments were designed to determine whether clofibrate reduces hypertension associated with chronic ET B receptor blockade. Male Sprague-Dawley rats received either normal-salt (0.8% NaCl) or high-salt (8% NaCl) diet for 10 days. Female rats were fed a high-salt (8% NaCl) diet for 10 days. During the last 7 days, rats of both sexes were divided into 3 treatment groups: (1) [1][2][3] In the kidney, ET-1 is synthesized from a variety of cells such as vascular endothelium, mesangial cells, tubular epithelial cells, and medullary interstitium. 4 -10 The primary receptor subtype on renal tubular epithelial cells is the ET B receptor. 3 Studies have demonstrated that ET-1 stimulates sodium and water excretion through ET B receptor activation. 11 Consistent with a pronatriuretic function, our laboratory has shown that blocking ET B receptors causes salt-dependent hypertension along with elevated plasma ET-1 levels. 12,13 The latter effect is thought to be attributable to reduced clearance of ET-1 in the absence of ET B receptor availability.The role of cytochrome P450 (CYP450) hydroxylase metabolites in the maintenance of arterial pressure is complex because of their contrasting hypertensive and antihypertensive properties. 14 Clofibrate, a peroxisome proliferator activated receptor-␣ (PPAR-␣) agonist, has been shown to reduce arterial pressure in Dahl salt-sensitive rats on high salt diet by inducing the genes that code for CYP4504A (CYP4A) enzymes in the renal cortex. 15,16 CYP4A is the enzyme responsible for the synthesis of 20-HETE. Interestingly, 20-HETE has actions to reduce sodium transport and, like ET B receptor activation, has been implicated in saltdependent hypertension. [17][18][19][20][21] Previous studies have provided evidence that 20-HETE contributes to ET-1-mediated natriuretic responses. 22 Blockade of CYP4A and 20-HETE prevented the increase in urinary sodium excretion produced by ET-1. 23 Similarly, inhibition of 20-HETE formation in isolated proximal tubules prevented the blockade of ion transport produced by ET-1, indicating that 20-HETE acts as a second messenger of ET-1 in the proximal tubule. 23 Because the ET-1-mediated diuretic and natriuretic effects are through ET B activation, it is reasonable to presume that ET-1 stimulates 20-HETE formation through ET B receptors. The purpose of the present study was to determine the influence of PPAR-␣ activation and upregulation of CYP4A in the salt-sensitive hypertension produced by chronic ET B receptor blockade.

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“…Since the effect of clofibrate is limited to saline treated rats, which are likely producing more EDHF in response to ACh, we believe that clofibrate potentiates EDHF. Clofibrate and other fibrates are peroxisome proliferator activated receptor-(PPAR ) agonists and have been shown to induce CYP 2C23 22 and increase epoxyeicosatrienoic acid production in the kidney. 23 Furthermore, in vitro studies revealed that incubation of endothelial cells with clofibrate for 72 hours causes membrane hyperpolarization, an effect attributed to EET formation.…”

Section: Sankaralingam Et Al Clofibrate Prevents Endothelial Dysfuncmentioning

confidence: 99%

Chronic clofibrate administration prevents salineinduced endothelial dysfunction and oxidative stress in young Sprague-Dawley rats

Sankaralingam

Desai²,

Wilson³

2008

CIM

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Clin Invest Med 2008; 31 (2): E62-E70. AbstractPurpose: High salt intake causes hypertension and endothelial dysfunction in young Sprague-Dawley rats. Clofibrate (clof) prevents this salt induced hypertension. We asked whether clof can prevent salt-induced endothelial dysfunction, and if so, its mechanism. We also questioned whether high salt intake can induce endothelial dysfunction without hypertension in older animals. Methods: Young (Y, 5 weeks) and old (O, 53 weeks) male Sprague-Dawley rats were given either vehicle (Con, 20 mM Na2CO3) or 0.9% NaCl (Sal) to drink for three weeks. Some young rats received clof (80 mg/d) in their drinking fluid. After three weeks, we measured mean arterial pressure (MAP), endothelial function, by comparing hypotensive responses to acetylcholine (ACh, endothelium dependent) and sodium nitroprusside (SNP, endothelium independent), plasma total nitrite+nitrate levels (PNOx), by the Griess reaction, and aortic superoxide production by lucigenin chemiluminescence. Results: Carotid artery MAP did not change in O. Sal-Y developed hypertension: 133±3 vs. 114±2 mmHg, P<0.001, which was prevented by clof: 105±2 mmHg . ACh induced a similar dose dependent hypotensive response in Con-O and Sal-O that was inhibited by L-NAME (100mg/kg i.v.). Responses to ACh were blunted in Sal-Y but not in Con-Y. Further, L-NAME inhibited ACh responses only in Con-Y. The response to SNP was similar in all animals. Importantly, the ACh-induced hypotensive response was potentiated in clof+Sal-Y, an effect which was attenuated by blocking calcium-activated potassium channels (KCa) with a combination of apamin (50 ug/kg i.v.) + charybdotoxin (50 ug/kg i.v.), but not by L-NAME. PNOx was reduced in Sal-Y compared to Con-Y (2.09±0.26 vs. 4.8±0.35 M, P<0.001), but not in Sal-O. Aortic superoxide production was higher (P<0.001) in Sal-Y (2388±40 milliunits/mg/min) than Sal-O (1107±159 milliunits/mg/ min), but was reduced by clof (1378±64 milliunits/mg/min; P<0.001). Conclusions: High salt intake increases oxidative stress in young animals, leading to impaired nitric oxide activity and endothelial dysfunction. Clofibrate prevents endothelial dysfunction partly through reduced O2˙-formation but mainly via selective activation of KCa channels. Older animals are resistant to both salt induced hypertension and oxidative stress.High salt intake can result in the development of hypertension in some humans 1 and animals. 2,3 High salt intake has also been reported to cause endothelial dysfunction, with or without a change in blood pressure. [4][5][6] Endothelial dysfunction is characterized by reduced endothelium dependent vascular relaxation. 7 Endothelium dependent vascular relaxa-

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A Peroxisome Proliferator-Activated Receptor-α Activator Induces Renal CYP2C23 Activity and Protects from Angiotensin II-Induced Renal Injury

Cited by 97 publications

References 45 publications

Roles of MEK/ERK Pathway in Vascular and Renal Tubular Actions of Angiotensin II

Roles of MEK/ERK Pathway in Vascular and Renal Tubular Actions of Angiotensin II

Peroxisome Proliferator-Activated Receptor-α Activation Reduces Salt-Dependent Hypertension During Chronic Endothelin B Receptor Blockade

Chronic clofibrate administration prevents salineinduced endothelial dysfunction and oxidative stress in young Sprague-Dawley rats

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