Abstract
Extracellular matrix expansion in the glomerular mesangium contributes to the development of glomerulosclerosis and chronic renal disease in arterial hypertension. Transforming growth factor-β1 (TGF-β1), 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 α-smooth muscle actin deposition. Quantification of mRNA levels in isolated glomeruli by real-time polymerase chain reaction showed a significant increase of TGF-β1, 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-β1, 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.
Footnotes
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This work was supported by Grant 01GS0416 from the Bundesministerium für Bildung und Forschung [Nationales Genomforschungsnetz (NGFN2), KGCV1] to R.K.
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doi:10.1124/jpet.105.093112.
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ABBREVIATIONS: ECM, extracellular matrix; MMP, matrix metalloproteinase; TIMP, tissue inhibitor of matrix metalloproteinase; Ang II, angiotensin II; RAS, renin-angiotensin-system; Ren2, TGR(mRen2)27; ACE, angiotensin-converting enzyme; MC, mesangial cell; TGF-β, transforming growth factor-β; SD, Sprague-Dawley; SBP, systolic blood pressure; UPE, urinary protein excretion; UAE, urinary albumin excretion; MME, mesangial matrix expansion; FGS, focal glomerular sclerosis; PBS, phosphate-buffered saline; α-SMA, α-smooth muscle actin; PCR, polymerase chain reaction; TBS, Tris-buffered saline.
- Received July 22, 2005.
- Accepted September 13, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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