PMID- 16166267 OWN - NLM STAT- MEDLINE DCOM- 20060331 LR - 20121115 IS - 0022-3565 (Print) IS - 0022-3565 (Linking) VI - 316 IP - 1 DP - 2006 Jan TI - 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. PG - 8-16 AB - 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. FAU - Bolbrinker, Juliane AU - Bolbrinker J AD - Department of Clinical Pharmacology, Charite-Universitatsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany. juliane.bolbrinker@charite.de FAU - Markovic, Snezana AU - Markovic S FAU - Wehland, Markus AU - Wehland M FAU - Melenhorst, Wynand B W H AU - Melenhorst WB FAU - van Goor, Harry AU - van Goor H FAU - Kreutz, Reinhold AU - Kreutz R LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20050915 PL - United States TA - J Pharmacol Exp Ther JT - The Journal of pharmacology and experimental therapeutics JID - 0376362 RN - 0 (Angiotensin-Converting Enzyme Inhibitors) RN - 0 (Matrix Metalloproteinase Inhibitors) RN - 0 (RNA, Messenger) RN - 0 (Tgfb1 protein, mouse) RN - 0 (Tgfb1 protein, rat) RN - 0 (Tissue Inhibitor of Metalloproteinase-1) RN - 0 (Transforming Growth Factor beta) RN - 0 (Transforming Growth Factor beta1) RN - 127497-59-0 (Tissue Inhibitor of Metalloproteinase-2) RN - 9000-70-8 (Gelatin) RN - EC 3.4.21.- (Serine Endopeptidases) RN - EC 3.4.21.- (prorenin Ren2 converting enzyme) RN - EC 3.4.24.24 (Matrix Metalloproteinase 2) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) SB - IM MH - Angiotensin-Converting Enzyme Inhibitors/*pharmacology MH - Animals MH - Animals, Genetically Modified MH - Blood Pressure/drug effects MH - Blotting, Western MH - Body Weight/drug effects/physiology MH - Gelatin/metabolism MH - Gene Expression Regulation, Enzymologic/drug effects/physiology MH - Glomerular Mesangium/*physiopathology MH - Hypertension/*physiopathology MH - Immunohistochemistry MH - Kidney Diseases/*physiopathology MH - Male MH - Matrix Metalloproteinase 2/*biosynthesis MH - Matrix Metalloproteinase 9/*biosynthesis MH - *Matrix Metalloproteinase Inhibitors MH - RNA, Messenger/biosynthesis MH - Rats MH - Rats, Sprague-Dawley MH - Renin-Angiotensin System/*physiology MH - Reverse Transcriptase Polymerase Chain Reaction MH - Serine Endopeptidases/genetics MH - Tissue Inhibitor of Metalloproteinase-1/physiology MH - Tissue Inhibitor of Metalloproteinase-2/physiology MH - Transforming Growth Factor beta/biosynthesis MH - Transforming Growth Factor beta1 EDAT- 2005/09/17 09:00 MHDA- 2006/04/01 09:00 CRDT- 2005/09/17 09:00 PHST- 2005/09/17 09:00 [pubmed] PHST- 2006/04/01 09:00 [medline] PHST- 2005/09/17 09:00 [entrez] AID - jpet.105.093112 [pii] AID - 10.1124/jpet.105.093112 [doi] PST - ppublish SO - J Pharmacol Exp Ther. 2006 Jan;316(1):8-16. doi: 10.1124/jpet.105.093112. Epub 2005 Sep 15.