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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.
J Pharmacol Exp Ther. 2006 Jan; 316(1):8-16.JP

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+Show Affiliations

Department of Clinical Pharmacology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany. juliane.bolbrinker@charite.deNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16166267

Citation

Bolbrinker, Juliane, et al. "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." The Journal of Pharmacology and Experimental Therapeutics, vol. 316, no. 1, 2006, pp. 8-16.
Bolbrinker J, Markovic S, Wehland M, et al. 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. J Pharmacol Exp Ther. 2006;316(1):8-16.
Bolbrinker, J., Markovic, S., Wehland, M., Melenhorst, W. B., van Goor, H., & Kreutz, R. (2006). 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. The Journal of Pharmacology and Experimental Therapeutics, 316(1), 8-16.
Bolbrinker J, et al. 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. J Pharmacol Exp Ther. 2006;316(1):8-16. PubMed PMID: 16166267.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Bolbrinker,Juliane, AU - Markovic,Snezana, AU - Wehland,Markus, AU - Melenhorst,Wynand B W H, AU - van Goor,Harry, AU - Kreutz,Reinhold, Y1 - 2005/09/15/ PY - 2005/9/17/pubmed PY - 2006/4/1/medline PY - 2005/9/17/entrez SP - 8 EP - 16 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 316 IS - 1 N2 - 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/16166267/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_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&amp;pmid=16166267 DB - PRIME DP - Unbound Medicine ER -