title: Local and systemic renin-angiotensin system participates in cardiopulmonary-renal interactions in monocrotaline-induced pulmonary hypertension in the rat.
abstract: Renin-angiotensin system (RAS) is one of the pathophysiological mechanisms in heart failure. Recently, involvement of the kidney in the disease progression has been proposed in patients with pulmonary arterial hypertension (PAH). We hypothesized that local and systemic RAS could be the central regulators of cardiopulmonary-renal interactions in experimental monocrotaline-induced pulmonary hypertension (PH) in rats. Male 12-week-old Wistar rats were injected subcutaneously with monocrotaline (60 mg/kg). The experiment was terminated 4 weeks after monocrotaline administration. Using RT-PCR, we measured the expression of RAS-related genes in right and left ventricles, lungs and kidneys, together with indicators of renal dysfunction and damage. We observed a significantly elevated expression of angiotensin-converting enzyme (ACE) in both left and right ventricles and kidneys (P < 0.05), but a significantly decreased ACE in the lungs (P < 0.05). Kidneys showed a significant 2.5-fold increase in renin mRNA (P < 0.05) along with erythropoietin, TGFβ1, COX-2, NOS-1 and nephrin. Expression of erythropoietin correlated inversely with hemoglobin oxygen saturation and positively with renin expression. In conclusion, monocrotaline-induced PH exhibited similar alterations of ACE expression in the left and right ventricles, and in the kidney, in contrast to the lungs. Increased renal renin was likely a consequence of renal hypoxia/hypoperfusion, as was increased renal erythropoietin expression. Alterations in RAS in the monocrotaline model are probably a result of hypoxic state, and while they could serve as a compensatory mechanism at a late stage of the disease, they could be viewed also as an indicator of multiorgan failure in PAH.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Odbojárov 10, 83232, Bratislava, Slovak Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Malikova
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Odbojárov 10, 83232, Bratislava, Slovak Republic.
authors.forename: Kristina
authors.initials: K
authors.lastname: Galkova
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Odbojárov 10, 83232, Bratislava, Slovak Republic.
authors.forename: Peter
authors.initials: P
authors.lastname: Vavrinec
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Odbojárov 10, 83232, Bratislava, Slovak Republic.
authors.forename: Diana
authors.initials: D
authors.lastname: Vavrincova-Yaghi
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Odbojárov 10, 83232, Bratislava, Slovak Republic.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Kmecova
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Odbojárov 10, 83232, Bratislava, Slovak Republic. krenek@fpharm.uniba.sk.
authors.forename: Peter
authors.initials: P
authors.lastname: Krenek
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Odbojárov 10, 83232, Bratislava, Slovak Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Klimas
mesh_terms: D000818:Animals; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008297:Male; D016686:Monocrotaline / Q000633:toxicity; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009928:Organ Specificity; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System
chemical_list: D016686:Monocrotaline; D007703:Peptidyl-Dipeptidase A
keywords: Angiotensin-converting enzyme; Erythropoietin; Kidney; Monocrotaline; Pulmonary hypertension; Renin–angiotensin system