TY - JOUR
T1 - Antifibrotic, nephroprotective potential of ACE inhibitor vs AT1 antagonist in a murine model of renal fibrosis
AU - Gross, Oliver
AU - Schulze-Lohoff, Eckhard
AU - Koepke, Marie-Louise
AU - Beirowski, Bogdan
AU - Addicks, Klaus
AU - Bloch, Wilhelm
AU - Smyth, Neil
AU - Weber, Manfred
PY - 2004/7/1
Y1 - 2004/7/1
N2 - BACKGROUND: Several studies have shown antifibrotic effects of angiotensin converting enzyme (ACE) inhibitors as well as of angiotensin receptor 1 (AT1) antagonists, however, prospective trials with clinical end points comparing these effects do not exist. COL4A3-/- mice develop a non-hypertensive progressive renal fibrosis. We used this animal model to compare the potential of ACE inhibitor vs AT1 antagonist to prevent renal fibrosis irrespective of blood pressure-dependent involvement by the renin system.METHODS: COL4A3-/- mice were treated with placebo, ramipril or candesartan. Blood pressure, proteinuria, serum urea and lifespan were monitored. Renal matrix was characterized by immuno-histochemistry, light and electron microscopy. Further biochemical analysis was provided using cDNA microarray and western blot techniques.RESULTS: Untreated mice died of renal failure after 71+/-6 days. Ramipril and candesartan both delayed onset and reduced the extent of proteinuria. Both had minor effects on blood pressure and postponed onset of uraemia. Ramipril increased lifespan by 111% to 150+/-21 days (P<0.01), whereas candesartan resulted in only a 38% prolongation to 98+/-16 days (P<0.01). Ramipril reduced glomerular and tubulo-interstitial fibrosis and numbers of activated fibroblasts to a greater extent than candesartan. Microarray and western blot analysis revealed a higher antifibrotic potential of ramipril in terms of downregulation of TGFbeta, connective tissue growth factor, metalloproteinases and extracellular matrix proteins.CONCLUSIONS: The results indicate an antifibrotic, nephroprotective effect of ACE inhibitors and AT1 antagonists in an animal model of progressive renal fibrosis. The greater antifibrotic effect of ramipril at the maximal therapeutic doses employed may not be explained by different antiproteinuric or blood pressure lowering properties, but by-in contrast to candesartan-its ability to hinder the proinflammatory, profibrotic activation of the angiotensin receptor 2.
AB - BACKGROUND: Several studies have shown antifibrotic effects of angiotensin converting enzyme (ACE) inhibitors as well as of angiotensin receptor 1 (AT1) antagonists, however, prospective trials with clinical end points comparing these effects do not exist. COL4A3-/- mice develop a non-hypertensive progressive renal fibrosis. We used this animal model to compare the potential of ACE inhibitor vs AT1 antagonist to prevent renal fibrosis irrespective of blood pressure-dependent involvement by the renin system.METHODS: COL4A3-/- mice were treated with placebo, ramipril or candesartan. Blood pressure, proteinuria, serum urea and lifespan were monitored. Renal matrix was characterized by immuno-histochemistry, light and electron microscopy. Further biochemical analysis was provided using cDNA microarray and western blot techniques.RESULTS: Untreated mice died of renal failure after 71+/-6 days. Ramipril and candesartan both delayed onset and reduced the extent of proteinuria. Both had minor effects on blood pressure and postponed onset of uraemia. Ramipril increased lifespan by 111% to 150+/-21 days (P<0.01), whereas candesartan resulted in only a 38% prolongation to 98+/-16 days (P<0.01). Ramipril reduced glomerular and tubulo-interstitial fibrosis and numbers of activated fibroblasts to a greater extent than candesartan. Microarray and western blot analysis revealed a higher antifibrotic potential of ramipril in terms of downregulation of TGFbeta, connective tissue growth factor, metalloproteinases and extracellular matrix proteins.CONCLUSIONS: The results indicate an antifibrotic, nephroprotective effect of ACE inhibitors and AT1 antagonists in an animal model of progressive renal fibrosis. The greater antifibrotic effect of ramipril at the maximal therapeutic doses employed may not be explained by different antiproteinuric or blood pressure lowering properties, but by-in contrast to candesartan-its ability to hinder the proinflammatory, profibrotic activation of the angiotensin receptor 2.
KW - Angiotensin II Type 1 Receptor Blockers
KW - Angiotensin-Converting Enzyme Inhibitors
KW - Animals
KW - Benzimidazoles
KW - Disease Models, Animal
KW - Fibrosis
KW - Hypertension, Renal
KW - Kidney
KW - Mice
KW - Ramipril
KW - Tetrazoles
KW - Time Factors
U2 - 10.1093/ndt/gfh219
DO - 10.1093/ndt/gfh219
M3 - Journal articles
C2 - 15128880
SN - 0931-0509
VL - 19
SP - 1716
EP - 1723
JO - Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
JF - Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
IS - 7
ER -