Atorvastatin enhances humoral immune responses but does not alter renal injury in experimental crescentic glomerulonephritis.
OBJECTIVE
Statins are widely used for their cholesterol-lowering effects and for prevention of cardiovascular disease. Evidence indicates that these drugs also have immunomodulatory and other non-lipid lowering effects, with studies suggesting benefit in some animal models of immune (particularly T helper (Th)1)-mediated inflammatory disease and their corresponding human disease counterparts. We sought to evaluate the immunomodulatory effects and therapeutic potential of atorvastatin in experimental crescentic glomerulonephritis, a Th1-predominant animal model of glomerulonephritis.


METHODS
Autologous phase, anti-glomerular basement membrane glomerulonephritis was induced in C57BL/6 mice by intravenous injection of sheep anti-mouse glomerular basement membrane globulin. Mice were administered atorvastatin (10 or 100 mg/kg) or control (phosphate-buffered saline) daily by oral gavage. Immune responses and renal injury were assessed after 21 days.


RESULTS
Compared with control-treated mice, treatment with atorvastatin did not alter renal injury (serum creatinine, proteinuria, glomerular crescent formation) or glomerular leukocytic infiltration (CD4(+) T cells or macrophages). Atorvastatin resulted in a dose-related increase in circulating serum antibody to the disease-inducing antigen but no differences in antigen-stimulated splenocyte production of Th1/Th2 cytokines. At the higher dose, atorvastatin also led to a significant reduction in apoptosis of splenic CD4(+) T lymphocytes.


CONCLUSIONS
This study demonstrates that statins modulate humoral responses and alter splenic CD4(+) T cell apoptosis. However, atorvastatin does not lead to significant changes in T helper cell polarization or renal injury in experimental crescentic glomerulonephritis.
Centre for Inflammatory Diseases, Monash University, Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia. rphoon@med.usyd.edu.au
Richard K S
RK
Phoon
A Richard
AR
Kitching
Lynelle K
LK
Jones
Stephen R
SR
Holdsworth
D000818:Animals; D000069059:Atorvastatin; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D056724:Immunity, Humoral / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011758:Pyrroles / Q000494:pharmacology*
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D000069059:Atorvastatin