title: Rosuvastatin is additive to high-dose candesartan in slowing progression of experimental mesangioproliferative glomerulosclerosis.
abstract: 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.
authors.affiliation: Dept. of Nephrology, Charité Universitätsmedizin Berlin, Campus Mitte, Humboldt Univ., Charitéplatz 1, D-10098 Berlin, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Krämer
authors.forename: Susanne
authors.initials: S
authors.lastname: Kron
authors.forename: Yingrui
authors.initials: Y
authors.lastname: Wang-Rosenke
authors.forename: Tanja
authors.initials: T
authors.lastname: Loof
authors.forename: Dmytro
authors.initials: D
authors.lastname: Khadzhynov
authors.forename: Stanislao
authors.initials: S
authors.lastname: Morgera
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawachi
authors.forename: Fujio
authors.initials: F
authors.lastname: Shimizu
authors.forename: Sebastian
authors.initials: S
authors.lastname: Martini
authors.forename: Hans-H
authors.initials: HH
authors.lastname: Neumayer
authors.forename: Harm
authors.initials: H
authors.lastname: Peters
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D004195:Disease Models, Animal; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005464:Fluorobenzenes / Q000627:therapeutic use*; D005923:Glomerulosclerosis, Focal Segmental / Q000503:physiopathology / Q000517:prevention & control*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology; D008297:Male; D011507:Proteinuria / Q000517:prevention & control; D011743:Pyrimidines / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000627:therapeutic use*; D013777:Tetrazoles / Q000627:therapeutic use*
chemical_list: D001562:Benzimidazoles; D001713:Biphenyl Compounds; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D013777:Tetrazoles; D000068718:Rosuvastatin Calcium; C081643:candesartan