title: Intrarenal alterations of the angiotensin-converting enzyme type 2/angiotensin 1-7 complex of the renin-angiotensin system do not alter the course of malignant hypertension in Cyp1a1-Ren-2 transgenic rats.
abstract: The role of the intrarenal renin-angiotensin system (RAS) in the pathophysiology of malignant hypertension is not fully understood. Accumulating evidence indicates that the recently discovered vasodilator axis of the RAS, angiotensin-converting enzyme (ACE) type 2 (ACE2)/angiotensin 1-7 (ANG 1-7), constitutes an endogenous system counterbalancing the hypertensiogenic axis, ACE/angiotensin II (ANG II)/AT1 receptor. This study aimed to evaluate the role of the intrarenal vasodilator RAS axis in the pathophysiology of ANG II-dependent malignant hypertension in Cyp1a1-Ren-2 transgenic rats. ANG II-dependent malignant hypertension was induced by 13 days' dietary administration of indole-3-carbinol (I3C), a natural xenobiotic that activates the mouse renin gene in Cyp1a1-Ren-2 transgenic rats. It was hypothesized that pharmacologically-induced inhibition of the ACE2/ANG 1-7 complex should aggravate, and activation of this axis should attenuate, the course of ANG II-dependent malignant hypertension. Blood pressure (BP) was monitored by radiotelemetry. ACE2 inhibitor (DX 600, 0.2 μg/day) and ACE2 activator (DIZE, 1 mg/day) were administrated via osmotic minipumps. Even though ACE2 inhibitor significantly decreased and ACE2 activator increased intrarenal ANG 1-7 concentrations, the course of BP, as well as of albuminuria, cardiac hypertrophy and renal glomerular damage, were not altered. It was shown that intrarenal alterations in the ACE2/ANG 1-7 complex did not significantly modify the course of malignant hypertension in I3C-induced Cyp1a1-Ren-2 transgenic rats. Thus, in our experimental setting alterations of this intrarenal vasodilator complex of the RAS do not significantly modify the form of malignant hypertension that clearly depends on the inappropriately increased activity of the ACE/ANG II/AT1 receptor axis.
authors.affiliation: Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Husková
authors.affiliation: Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Libor
authors.initials: L
authors.lastname: Kopkan
authors.affiliation: Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Lenka
authors.initials: L
authors.lastname: Červenková
authors.affiliation: Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Šárka
authors.initials: Š
authors.lastname: Doleželová
authors.affiliation: Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Zdeňka
authors.initials: Z
authors.lastname: Vaňourková
authors.affiliation: Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Škaroupková
authors.affiliation: Department of Pharmacology, Kagawa University, Kagawa, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.affiliation: Department of Renal and Body Fluid Physiology, Mossakowski Medical Research Centre, Polish Academy of Science, 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 Science, Warsaw, Poland.
authors.forename: Janusz
authors.initials: J
authors.lastname: Sadowski
authors.affiliation: Section of Nephrology, Department of Medicine, University of Bonn, Bonn, Germany.
authors.forename: Herbert J
authors.initials: HJ
authors.lastname: Kramer
authors.affiliation: Centre 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: Luděk
authors.initials: L
authors.lastname: Červenka
mesh_terms: D000419:Albuminuria / Q000150:complications; D000803:Angiotensin I / Q000378:metabolism*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D004133:Diminazene / Q000031:analogs & derivatives / Q000494:pharmacology; D020536:Enzyme Activators / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006974:Hypertension, Malignant / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology / Q000652:urine; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D051381:Rats; D055647:Rats, Transgenic; D012083:Renin / Q000235:genetics; D012084:Renin-Angiotensin System / Q000187:drug effects*; D012964:Sodium / Q000652:urine
chemical_list: C556151:DX600 peptide; D020536:Enzyme Activators; D010446:Peptide Fragments; D010455:Peptides; C473112:Ren2 protein, mouse; D000803:Angiotensin I; D012964:Sodium; D019363:Cytochrome P-450 CYP1A1; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; D012083:Renin; C118790:angiotensin I (1-7); C003915:diminazene aceturate; D004133:Diminazene
keywords: angiotensin 1-7; angiotensin II; angiotensin-converting enzyme type 2; malignant hypertension; renin-angiotensin system