Simvastatin suppresses glomerular cell proliferation and macrophage infiltration in rats with mesangial proliferative nephritis.
Inhibition of 3-hydro-3-methylglutaryl coenzyme A reductase inhibits the production of mevalonate and has been shown to suppress proliferation in many cell types. Therefore, 3-hydro-3-methylglutaryl coenzyme A reductase inhibitors may have a beneficial effect in glomerular disease, because glomerular cell proliferation is a central feature in the active glomerular injury. This study examines the effect of simvastatin on glomerular pathology in a rat mesangial proliferative glomerulonephritis (GN) induced by anti-thymocyte antibody (anti-Thy 1.1 GN). There was no difference in the degree of the antibody and complement-mediated initial injuries between simvastatin-treated and control GN rats. The most pronounced feature of simvastatin-treated GN was the suppression of the early glomerular cell proliferation. The proliferative activity was maximal at day 4 after disease induction (26.5+/-7.0 of proliferating cell nuclear antigen-positive cells/glomerulus); however, approximately 70% of proliferation was suppressed by simvastatin treatment. At day 4 after disease induction, simvastatin administration also decreased alpha-smooth muscle actin expression in the glomerulus, which is a marker for mesangial cell activation. Inhibition of monocyte/macrophage recruitment into glomeruli by simvastatin was also a prominent feature. There was a 30% decrease in the number of glomerular ED-1+ cells by simvastatin treatment at day 2 after disease induction. Furthermore, simvastatin remarkably suppressed subsequent mesangial matrix expansion and type IV collagen accumulation in glomeruli. We also found that the platelet-derived growth factor expression was reduced in simvastatin-treated nephritic rats, which might simply reflect the reduction in mesangial cell proliferation and mesangial cellularity. There was no significant difference in plasma cholesterol or triglyceride levels between simvastatin- and vehicle-treated nephritic rats at day 2 and day 4, which corresponded to the times when simvastatin treatment resulted in a reduction in mesangial cell proliferation. In conclusion, this is the first report to find that mesangial cell proliferation and matrix expansion have been blocked by simvastatin in vivo. The protective effect of simvastatin in the matrix expansion in anti-Thy1.1 GN was partly by inhibition of mesangial cell proliferation and monocyte/ macrophage recruitment into glomeruli, which were independent of a change in circulating lipids.
Yoshimura
A
A
Department of Medicine, Showa University Fujigaoka Hospital, Yokohama, Japan.
Inui
K
K
Nemoto
T
T
Uda
S
S
Sugenoya
Y
Y
Watanabe
S
S
Yokota
N
N
Taira
T
T
Iwasaki
S
S
Ideura
T
T
D000199:Actins / Q000378:metabolism; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D005109:Extracellular Matrix / Q000378:metabolism; D005920:Glomerular Mesangium / Q000187:drug effects / Q000473:pathology*; D005921:Glomerulonephritis / Q000473:pathology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D009130:Muscle, Smooth / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D011507:Proteinuria / Q000652:urine; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D019821:Simvastatin / Q000494:pharmacology*
D000199:Actins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D003094:Collagen; D019821:Simvastatin; D003404:Creatinine