Statin attenuates experimental anti-glomerular basement membrane glomerulonephritis together with the augmentation of alternatively activated macrophages.
Macrophages are heterogeneous and include classically activated M1 and alternatively activated M2 macrophages, characterized by pro- and anti-inflammatory functions, respectively. Macrophages that express heme oxygenase-1 also exhibit anti-inflammatory effects. We assessed the anti-inflammatory effects of statin in experimental anti-glomerular basement membrane glomerulonephritis and in vitro, focusing on the macrophage heterogeneity. Rats were induced anti-glomerular basement membrane glomerulonephritis and treated with atorvastatin (20 mg/kg/day) or vehicle (control). Control rats showed infiltration of macrophages in the glomeruli at day 3 and developed crescentic glomerulonephritis by day 7, together with increased mRNA levels of the M1 macrophage-associated cytokines, interferon-gamma, tumor necrosis factor-alpha, and interleukin-12. In contrast, statin reduced the level of proteinuria, reduced infiltration of macrophages in glomeruli with suppression of monocyte chemotactic protein-1 expression, and inhibited the formation of necrotizing and crescentic lesions. The number of glomerular ED3-positive macrophages decreased with down-regulation of M1 macrophage-associated cytokines. Furthermore, statin augmented ED2-positive M2 macrophages with up-regulation of the M2 macrophage-associated chemokines and cytokines, chemokine (C-C motif) Iigand-17 and interleukin-10. Statin also increased the glomerular interleukin-10-expressing heme oxygenase-1-positive macrophages. Statin inhibited macrophage development, and suppressed ED3-positive macrophages, but augmented ED2-positive macrophages in M2-associated cytokine environment in vitro. We conclude that the anti-inflammatory effects of statin in glomerulonephritis are mediated through inhibition of macrophage infiltration as well as augmentation of anti-inflammatory macrophages.
Fujita
Emiko
E
Department of Analytic Human Pathology, Nippon Medical School, Tokyo, Japan.
Shimizu
Akira
A
Masuda
Yukinari
Y
Kuwahara
Naomi
N
Arai
Takashi
T
Nagasaka
Shinya
S
Aki
Kaoru
K
Mii
Akiko
A
Natori
Yasuhiro
Y
Iino
Yasuhiko
Y
Katayama
Yasuo
Y
Fukuda
Yuh
Y
D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000069059:Atorvastatin; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D050533:Glomerular Basement Membrane / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D007150:Immunohistochemistry; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008854:Microscopy, Electron; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric
D016207:Cytokines; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D012333:RNA, Messenger; D000069059:Atorvastatin