Preventive effect of cerivastatin on diabetic nephropathy through suppression of glomerular macrophage recruitment in a rat model.
OBJECTIVE
We investigated the effect of cerivastatin, a statin, on the development of diabetic nephropathy in spontaneously hypertensive rats (SHR) with streptozotocin-induced diabetes.


METHODS
Diabetic SHR were given standard chow or chow containing cerivastatin at a dose of 0.1 mg/kg or 1.0 mg/kg for 12 weeks. Effects of cerivastatin on urinary albumin excretion, mesangial expansion, glomerular macrophage infiltration, and the number of anionic sites on the glomerular basement membrane (GBM) were assessed.


RESULTS
Cerivastatin did not affect the blood glucose concentration, blood pressure or serum cholesterol concentration in diabetic SHR. However, cerivastatin treatment caused a dose-dependent decrease of albuminuria and hyperfiltration. At 1.0 mg/kg, cerivastatin inhibited the diabetes-induced expansion of mesangial and tuft areas on histological examination of the kidneys, as well as the loss of anionic sites from the GBM evaluated with polyetyleneimine and the intraglomerular infiltration of ED1-positive macrophages evaluated by immunohistochemistry. Whole-kidney expression of mRNA for MCP-1 and TGF-beta, estimated by the real-time quantitative RT-PCR, was increased (both 2.6-fold) in untreated diabetic SHR at 12 weeks. Cerivastatin treatment (1.0 mg/kg) inhibited the up-regulated expression of MCP-1 and TGF-beta mRNA (decreased to 48% and 34%, respectively) in diabetic SHR.


CONCLUSIONS
In this hypertensive model of diabetic nephropathy, cerivastatin decreased albuminuria through suppression of glomerular hyperfiltration, mesangial expansion, and the loss of charge barrier independently of a cholesterol-lowering effect. These preventive effects could be at least partly due to inhibition of macrophage recruitment and activation, and inhibition of TGF-beta overexpression.
Ota
T
T
Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8641, Japan.
Takamura
T
T
Ando
H
H
Nohara
E
E
Yamashita
H
H
Kobayashi
K
K
D000818:Animals; D001483:Base Sequence; D018932:Chemokine CCL2 / Q000235:genetics; D017931:DNA Primers; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology* / Q000517:prevention & control; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007678:Kidney Glomerulus / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000473:pathology*; D008297:Male; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D013237:Stereoisomerism; D016212:Transforming Growth Factor beta / Q000235:genetics
D018932:Chemokine CCL2; D017931:DNA Primers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011725:Pyridines; D016212:Transforming Growth Factor beta; C086276:cerivastatin