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

• Published in: American journal of physiology. Renal physiology 2008-04, Vol.294 (4), p.F801-F811
• Main Authors: Krämer, Stephanie, Kron, Susanne, Wang-Rosenke, Yingrui, Loof, Tanja, Khadzhynov, Dmytro, Morgera, Stanislao, Kawachi, Hiroshi, Shimizu, Fujio, Martini, Sebastian, Neumayer, Hans-H, Peters, Harm
• Format: Article
• Language: English
• Subjects: Animals; Benzimidazoles - therapeutic use; Cells; Disease Models, Animal; Disease Progression; Drug therapy; Drug Therapy, Combination; Fluorobenzenes - therapeutic use; Gene expression; Glomerulosclerosis, Focal Segmental - physiopathology; Glomerulosclerosis, Focal Segmental - prevention & control; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Kidney Glomerulus - drug effects; Kidney Glomerulus - pathology; Kidneys; Male; Nephrology; Proteinuria - prevention & control; Pyrimidines - therapeutic use; Rats; Rats, Wistar; Rosuvastatin Calcium; Sulfonamides - therapeutic use; Tetrazoles - therapeutic use
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00148.2007

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 AT(1) 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)-beta served as the main marker of disease progression. Compared with the untreated GS rats (475 +/- 52 pg/ml), tubulointerstitial TGF-beta(1) 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-beta(1) 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 AT(1) antagonist candesartan. Combined treatment yields significantly greater actions on renal TGF-beta overexpression and matrix accumulation, cell proliferation, and macrophage infiltration. The results suggest that rosuvastatin and an AT(1) blocker independently interfere with separate key pathways involved in the progression of chronic mesangioproliferative GS.