title: Fenofibrate Attenuates Malignant Hypertension by Suppression of the Renin-angiotensin System: A Study in Cyp1a1-Ren-2 Transgenic Rats.
abstract: BACKGROUND
  Malignant hypertension is a life-threatening condition, and its pathophysiology is still poorly understood. The present study was designed to evaluate the role of interaction of the renin-angiotensin system with 20-hydroxyeicosatetraenoic acid (20-HETE), a product of cytochrome P450 (CYP)-dependent ω-hydroxylase pathway, in the pathophysiology of angiotensin II (ANG II)-dependent malignant hypertension in Cyp1a1-Ren-2 transgenic rats.
  
  
  METHODS
  Malignant hypertension was induced by 12 days׳ dietary administration of 0.3 % indole-3-carbinol (I3C), a natural xenobiotic that activates a mouse renin gene. We hypothesized that chronic administration of fenofibrate, 190mg/kg body weight, a lipid-lowering drug, should increase renal production of 20-HETE, a tubular transport inhibitor; an expected increase in sodium excretion would oppose the development of ANG II-dependent malignant hypertension. Blood pressure was monitored by radiotelemetry, and at the end of the experiment rats were prepared for renal functional studies to evaluate in vivo the pressure-natriuresis relationship in response to stepwise reductions in renal arterial pressure (RAP).
  
  
  RESULTS
  In I3C-induced rats, the treatment with fenofibrate significantly attenuated hypertension and improved the slope of the pressure-natriuresis relationship. Although fenofibrate treatment increased kidney gene and protein expression of CYP4A1, a major isoform responsible for 20-HETE formation, it did not increase renal 20-HETE concentration. On the contrary, fenofibrate treatment significantly suppressed renin gene expression, plasma renin activity and plasma and kidney ANG II levels.
  
  
  CONCLUSIONS
  Fenofibrate treatment significantly attenuated the course of malignant hypertension in I3C-induced CYP1a1-Ren-2 transgenic rats, and the mechanism responsible for antihypertensive action was fenofibrate-induced suppression of renin-angiotensin system activity.
authors.affiliation: Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; Department of Pathophysiology, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Šárka
authors.initials: Š
authors.lastname: Jíchová
authors.affiliation: Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Šárka
authors.initials: Š
authors.lastname: Doleželová
authors.affiliation: Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Libor
authors.initials: L
authors.lastname: Kopkan
authors.affiliation: Department of Renal and Body Fluid Physiology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Kompanowska-Jezierska
authors.affiliation: Department of Renal and Body Fluid Physiology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Janusz
authors.initials: J
authors.lastname: Sadowski
authors.affiliation: Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; Department of Pathophysiology, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic. Electronic address: luce@medicon.cz.
authors.forename: Luděk
authors.initials: L
authors.lastname: Červenka
mesh_terms: D000818:Animals; D001794:Blood Pressure; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D042926:Cytochrome P-450 CYP4A / Q000378:metabolism; D011345:Fenofibrate / Q000494:pharmacology / Q000627:therapeutic use*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D006974:Hypertension, Malignant / Q000139:chemically induced / Q000188:drug therapy*; D007211:Indoles; D007668:Kidney / Q000378:metabolism; D008297:Male; D009318:Natriuresis / Q000187:drug effects*; D055647:Rats, Transgenic; D012079:Renal Circulation / Q000187:drug effects; D012083:Renin / Q000235:genetics; D012084:Renin-Angiotensin System / Q000187:drug effects*; D015533:Transcriptional Activation
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; D007211:Indoles; C535029:Ren2 protein, rat; C016517:indole-3-carbinol; D019363:Cytochrome P-450 CYP1A1; D042926:Cytochrome P-450 CYP4A; D012083:Renin; D011345:Fenofibrate
keywords: 20-hydroxyeicosatetraenoic acid; Cytochrome P450 metabolites; Malignant hypertension; Renin-angiotensin system