title: Expression and response to angiotensin-converting enzyme inhibition of matrix metalloproteinases 2 and 9 in renal glomerular damage in young transgenic rats with renin-dependent hypertension.
abstract: Extracellular matrix expansion in the glomerular mesangium contributes to the development of glomerulosclerosis and chronic renal disease in arterial hypertension. Transforming growth factor-beta1 (TGF-beta1), matrix metalloproteinases (MMPs), and tissue inhibitors of MMPs (TIMPs) are involved in this process. Conflicting data are reported on the effects of angiotensin II (Ang II) and the response to angiotensin-converting enzyme inhibition on MMPs and TIMPs in early stages of hypertensive glomerular damage. We therefore investigated the effects of Ang II-dependent hypertension on MMP-2, MMP-9, TIMP-1, and TIMP-2 in isolated glomeruli of 8-week-old homozygous male rats overexpressing the mouse Ren2 gene [TGR(mRen2)27]. At this age, systolic blood pressure was already significantly elevated in Ren2 compared with Sprague-Dawley (SD) rats (197 +/- 38 versus 125 +/- 16 mm Hg, p < 0.01). Ren2 exhibited renal damage as determined by increased urinary albumin excretion, focal glomerulosclerosis, mesangial matrix expansion, and alpha-smooth muscle actin deposition. Quantification of mRNA levels in isolated glomeruli by real-time polymerase chain reaction showed a significant increase of TGF-beta1, a 2.3- and a 2.6-fold increase of MMP-2 and TIMP-1 in Ren2 compared with SD (p < 0.01, respectively) and no strain differences for TIMP-2. In contrast, MMP-9 mRNA expression was markedly suppressed to 10% of control levels in Ren2 (p < 0.01). Early treatment with ramipril completely prevented renal damage in Ren2 and restored mRNA expression of TGF-beta1, MMP-2, and TIMP-1 to SD control levels. Interestingly, down-regulation of MMP-9 mRNA, protein, and activity was not affected by ramipril, indicating that the protective effect of this compound is not attributable to restoration of MMP-9 in the glomerulus.
authors.affiliation: Department of Clinical Pharmacology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany. juliane.bolbrinker@charite.de
authors.forename: Juliane
authors.initials: J
authors.lastname: Bolbrinker
authors.forename: Snezana
authors.initials: S
authors.lastname: Markovic
authors.forename: Markus
authors.initials: M
authors.lastname: Wehland
authors.forename: Wynand B W H
authors.initials: WB
authors.lastname: Melenhorst
authors.forename: Harry
authors.initials: H
authors.lastname: van Goor
authors.forename: Reinhold
authors.initials: R
authors.lastname: Kreutz
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D030801:Animals, Genetically Modified; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D005780:Gelatin / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D005920:Glomerular Mesangium / Q000503:physiopathology*; D006973:Hypertension / Q000503:physiopathology*; D007150:Immunohistochemistry; D007674:Kidney Diseases / Q000503:physiopathology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000235:genetics; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000502:physiology; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D053773:Transforming Growth Factor beta1
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; C508961:Tgfb1 protein, mouse; C508962:Tgfb1 protein, rat; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D019716:Tissue Inhibitor of Metalloproteinase-2; D005780:Gelatin; D012697:Serine Endopeptidases; C063570:prorenin Ren2 converting enzyme; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9