Fenofibrate Attenuates Malignant Hypertension by Suppression of the Renin-angiotensin System: A Study in Cyp1a1-Ren-2 Transgenic Rats

Jíchová, Šárka; Doleželová, Šárka; Kopkan, Libor; Kompanowska-Jezierska, Elżbieta; Sadowski, Janusz; Červenka, Luděk

doi:10.1016/j.amjms.2016.09.008

Cited by 19 publications

(21 citation statements)

References 49 publications

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“…However, this interpretation seems difficult to reconcile with our present and recent findings that after induction of renin gene intrarenal concentrations of 20-HETE are actually decreased in Cyp1a1-Ren-2 transgenic rats. Similar to our previous study [ 40 ], we observed that lower renal levels of 20-HETE in our model of malignant hypertension does not depend on SBP or ANG II levels. Both 20-HETE receptor antagonist and AT1 receptor inhibitor did not affected 20-HETE levels in the kidney in Cyp1a1-Ren-2 transgenic rats.…”

Section: Discussionsupporting

confidence: 92%

“…In accordance with the recommendation for BP measurement in experimental animals, we employed a radiotelemetry system [ 42 ]. Rats were anesthetized with a combination of tiletamine, zolazepam (Zoletil, Virbac SA, Carros Cedex, France; 8 mg.kg −1 ), and xylazine (Rometar, Spofa, Czech Republic; 4 mg.kg −1 ) intramuscularly, and TA11PA-C40 radiotelemetric probes (Data Sciences International, St. Paul, MN, U.S.A.) were implanted for direct BP measurements as described previously [ 34 , 39 , 40 ]. The rats were allowed 10 days to recover before basal BP was recorded and only animals with stable BP records at the end of this recovery period were used for experiments.…”

Section: Methodsmentioning

confidence: 99%

“…The treatment with 20-HETE antagonist or AT 1 receptor blocker was started simultaneously with initiation of dietary administration of I3C. In the animals implanted with radiotransmitters, 24-h urine collections were performed in metabolic cages prior (day 3) and during (days 3 and 10) the experiments by methods described previously [ 31 , 34 , 39 , 40 , 43 ]. At the end of experiments, all rats were killed with an overdose of thiopental sodium (Sandoz, Basel, Switzerland) and the kidneys were removed for assessment of renal injury.…”

Section: Methodsmentioning

confidence: 99%

“…The organic extracts were evaporated to dryness under reduced pressure and reconstituted in methanol for HPLC purification on an Agilent 1200SL system. In addition, kidney concentrations of epoxyeicosatrienoic acids (EETs) and their metabolites (dihydroxyeicosatrienoic acids (DHETEs)), specifically 5,6-EETs; 8,9-EETs; 11,12-EETs; and 14,15-EETs were measured separately and then pooled for final presentation of the EETs/DHETEs ratio as described previously [ 40 , 45 , 50 ]. The results were corrected to gram of protein.…”

Section: Methodsmentioning

confidence: 99%

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20-Hydroxyeicosatetraenoic acid antagonist attenuates the development of malignant hypertension and reverses it once established: a study in Cyp1a1-Ren-2 transgenic rats

et al. 2018

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We hypothesized that vascular actions of 20-hydroxyeicosatetraenoic acid (20-HETE), the product of cytochrome P450 (CYP450)-dependent ω-hydroxylase, potentiate prohypertensive actions of angiotensin II (ANG II) in Cyp1a1-Ren-2 transgenic rats, a model of ANG II-dependent malignant hypertension. Therefore, we evaluated the antihypertensive effectiveness of 20-HETE receptor antagonist (AAA) in this model. Malignant hypertension was induced in Cyp1a1-Ren-2 transgenic rats by activation of the renin gene using indole-3-carbinol (I3C), a natural xenobiotic. Treatment with AAA was started either simultaneously with induction of hypertension or 10 days later, during established hypertension. Systolic blood pressure (SBP) was monitored by radiotelemetry, indices of renal and cardiac injury, and kidney ANG II levels were determined. In I3C-induced hypertensive rats, early AAA treatment reduced SBP elevation (to 161 ± 3 compared with 199 ± 3 mmHg in untreated I3C-induced rats), reduced albuminuria, glomerulosclerosis index, and cardiac hypertrophy (P<0.05 in all cases). Untreated I3C-induced rats showed augmented kidney ANG II (405 ± 14 compared with 52 ± 3 fmol/g in non-induced rats, P<0.05) which was markedly lowered by AAA treatment (72 ± 6 fmol/g). Remarkably, in TGR with established hypertension, AAA also decreased SBP (from 187 ± 4 to 158 ± 4 mmHg, P<0.05) and exhibited organoprotective effects in addition to marked suppression of kidney ANG II levels. In conclusion, 20-HETE antagonist attenuated the development and largely reversed the established ANG II-dependent malignant hypertension, likely via suppression of intrarenal ANG II levels. This suggests that intrarenal ANG II activation by 20-HETE is important in the pathophysiology of this hypertension form.

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Section: Discussionsupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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20-Hydroxyeicosatetraenoic acid antagonist attenuates the development of malignant hypertension and reverses it once established: a study in Cyp1a1-Ren-2 transgenic rats

et al. 2018

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“…11,117 Fenofibrate also enhances renal 20-HETE levels and attenuates hypertension in ANG II-infused mice, Ren-2 hypertensive rats, and stroke-prone SHR or SHR. [121][122][123][124] A summary of the roles of 20-HETE and EETs in hypertension is presented in Figure 3. We hypothesize that decreases in the renal formation of 20-HETE in Dahl S rats and patients with inactivating mutations in CYP4A11 and CYP4F2 promote the development of salt-sensitive hypertension.…”

Section: -Hete and Hypertensionmentioning

confidence: 99%

Effect of Cytochrome P450 Metabolites of Arachidonic Acid in Nephrology

Fan

Roman

2017

JASN

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Thirty-five years ago, a third pathway for the metabolism of arachidonic acid by cytochrome P450 enzymes emerged. Subsequent work revealed that 20-hydroxyeicosatetraenoic and epoxyeicosatrienoic acids formed by these pathways have essential roles in the regulation of renal tubular and vascular function. Sequence variants in the genes that produce 20-hydroxyeicosatetraenoic acid are associated with hypertension in humans, whereas the evidence supporting a role for variants in the genes that alter levels of epoxyeicosatrienoic acids is less convincing. Studies in animal models suggest that changes in the production of cytochrome P450 eicosanoids alter BP. However, the mechanisms involved remain controversial, especially for 20-hydroxyeicosatetraenoic acid, which has both vasoconstrictive and natriuretic actions. Epoxyeicosatrienoic acids are vasodilators with anti-inflammatory properties that oppose the development of hypertension and CKD; 20-hydroxyeicosatetraenoic acid levels are elevated after renal ischemia and may protect against injury. Levels of this eicosanoid are also elevated in polycystic kidney disease and may contribute to cyst formation. Our review summarizes the emerging evidence that cytochrome P450 eicosanoids have a role in the pathogenesis of hypertension, polycystic kidney disease, AKI, and CKD.

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Fenofibrate Attenuates Hypertension in Goldblatt Hypertensive Rats: Role of 20-Hydroxyeicosatetraenoic Acid in the Nonclipped Kidney

Sporková

Chábová

Doleželová

et al. 2017

The American Journal of the Medical Sciences

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Fenofibrate Attenuates Malignant Hypertension by Suppression of the Renin-angiotensin System: A Study in Cyp1a1-Ren-2 Transgenic Rats

Cited by 19 publications

References 49 publications

20-Hydroxyeicosatetraenoic acid antagonist attenuates the development of malignant hypertension and reverses it once established: a study in Cyp1a1-Ren-2 transgenic rats

20-Hydroxyeicosatetraenoic acid antagonist attenuates the development of malignant hypertension and reverses it once established: a study in Cyp1a1-Ren-2 transgenic rats

Effect of Cytochrome P450 Metabolites of Arachidonic Acid in Nephrology

Fenofibrate Attenuates Hypertension in Goldblatt Hypertensive Rats: Role of 20-Hydroxyeicosatetraenoic Acid in the Nonclipped Kidney

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