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This Article Full Text Full Text (PDF) All Versions of this Article: 294/4/F801    most recent 00148.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Krämer, S. Articles by Peters, H. PubMed PubMed Citation Articles by Krämer, S. Articles by Peters, H.

Rosuvastatin is additive to high-dose candesartan in slowing progression of experimental mesangioproliferative glomerulosclerosis

¹Department of Nephrology and Center for Cardiovascular Research, Charité Universitätsmedizin Berlin, Humboldt University, Berlin, Germany; and ²Department of Cell Biology and Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

Submitted 30 March 2007 ; accepted in final form 14 December 2007

Rosuvastatin is additive to high-dose candesartan in slowing progression of experimental mesangioproliferative glomerulosclerosis (GS). Progressive mesangioproliferative glomerulonephritis, mostly IgA nephropathy, is a major cause of end-stage kidney disease worldwide. In a chronic-progressive model of mesangioproliferative GS, we tested the renoprotective efficacy of rosuvastatin alone and in combination with a high-dose of the AT₁ blocker candesartan. Treatment was started 1 wk after disease induction (anti-thy1 antibody injection into uninephrectomized rats) and continued until week 20. Tubulointerstitial expression of the key fibrosis mediator transforming growth factor (TGF)-β served as the main marker of disease progression. Compared with the untreated GS rats (475 ± 52 pg/ml), tubulointerstitial TGF-β₁ protein expression was significantly reduced by both single therapies (rosuvastatin –47%, candesartan –51%, P < 0.01). Tubulointerstitial matrix accumulation (matrix score in GS: 64 ± 7%) was relatively reduced by –45 and –52%, respectively (P < 0.01). The combination of rosuvastatin and candesartan had significantly greater effects on tubulointerstitial TGF-β₁ expression (–82% vs. GS) and matrix accumulation (–83% vs. GS) (P < 0.001 vs. GS, P < 0.05 vs. single therapy) than either drug alone. Similar additive beneficial effects were observed for renal fibronectin and tissue inhibitor of metalloproteinase-1 expression, cell proliferation, macrophage infiltration, proteinuria, and kidney function. In conclusion, rosuvastatin limits the progressive course of anti-thy1-induced GS toward chronic tubulointerstitial fibrosis and renal insufficiency to a degree comparable to the one achieved by a high dose of the AT₁ antagonist candesartan. Combined treatment yields significantly greater actions on renal TGF-β overexpression and matrix accumulation, cell proliferation, and macrophage infiltration. The results suggest that rosuvastatin and an AT₁ blocker independently interfere with separate key pathways involved in the progression of chronic mesangioproliferative GS.

renal fibrosis; transforming growth factor-β₁; IgA nephropathy