title: Interstitial fibrosis and microvascular disease of the heart in uremia: amelioration by a calcimimetic.
abstract: In patients with chronic renal failure, the heart undergoes remodeling, characterized by hypertrophy, fibrosis, and capillary/myocyte mismatch. In this study, we observed the effects of the calcimimetic agent R-568 on microvascular disease and interstitial fibrosis of the heart. Three-month-old male Sprague-Dawley rats were randomized to subtotal nephrectomy (SNX) or sham operation and subsequently received vehicle or R-568 under two experimental protocols, one for 1 month and the other for 3 months. Echocardiography, capillary length density, volume density of interstitial tissue, and immunohistochemistry and western blots (calcium-sensing receptor, collagen I and III, transforming growth factor (TGF)-beta, mitogen-activated protein kinases, and nitrotyrosine) were assessed. After SNX, weight and wall thickness of the left and the right ventricle were elevated. The ratio of heart to body weight and interventricular septum thickness were not changed by R-568 treatment. The left ventricle fractional shortening (by echocardiography) was lower in SNX; this was ameliorated by R-568. Reduced capillary length density and increased interstitial fibrosis in SNX were improved by R-568, which also reduced the expression of TGF-beta, and collagen I and III. The calcimimetic increased the activation of ERK-1/2, normalized p38 and JNK signaling, and prevented oxidative stress. We conclude that lowering parathyroid hormone with a calcimimetic significantly improves cardiac histology and function but not the left ventricular mass in SNX.
authors.affiliation: Insitute of Pathology, University of Heidelberg, Heidelberg, Germany. nad_ko@gmx.de
authors.forename: Nadezda
authors.initials: N
authors.lastname: Koleganova
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Piecha
authors.forename: Eberhard
authors.initials: E
authors.lastname: Ritz
authors.forename: Raffi
authors.initials: R
authors.lastname: Bekeredjian
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Claus Peter
authors.initials: CP
authors.lastname: Schmitt
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Gross
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002118:Calcium / Q000819:agonists* / Q000378:metabolism; D002196:Capillaries / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects; D004730:Endothelium, Vascular / Q000378:metabolism; D004789:Enzyme Activation; D005355:Fibrosis; D006321:Heart / Q000187:drug effects*; D006331:Heart Diseases / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000473:pathology; D009392:Nephrectomy; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress; D010627:Phenethylamines; D010758:Phosphorus / Q000378:metabolism; D011437:Propylamines; D051381:Rats; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing / Q000378:metabolism; D014511:Uremia / Q000150:complications* / Q000188:drug therapy
chemical_list: D000814:Aniline Compounds; D015415:Biomarkers; C107873:N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine; D010627:Phenethylamines; D011437:Propylamines; D044169:Receptors, Calcium-Sensing; D010758:Phosphorus; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium