Fluvastatin inhibits high glucose-induced nuclear factor kappa B activation in renal tubular epithelial cells.
BACKGROUND
3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been shown to reduce the progression of renal disease independent of cholesterol-lowering effect, but the mechanism of the potential protective effect remains unclear. Here, we investigate the effect of fluvastatin on activation of nuclear factor-kappaB (NF-kappaB) induced by high glucose in rat kidney tubule epithelial cells in vivo and in vitro.


METHODS
Streptozotocin (STZ)-induced uninephrectomized diabetic rats were treated daily with fluvastatin (4 mg/kg body weight) by gavage. In 8 weeks the animals were killed, and their urine and blood samples were collected. Blood glucose, blood lipid, the urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG), albumin and creatinine were measured. Immunohistochemical staining of NF-kappaB in the tubulointerstitium was performed. Rat renal tubular epithelial cells (NRK-52E) were cultured under normal glucose, high glucose (HG) and HG with fluvastatin or SB202190 (a specific inhibitor of p38MAPK) or mevalonate. Electrophoretic mobility shift assay (EMSA) was used to detect NF-kappaB activation. Phosphorylation of cellular p38 mitogen-activated protein kinase (p38MAPK) was determined by Western blot analysis.


RESULTS
Compared with that in the control group, the expression of NF-kappaB increased in tubulointerstitium of experimental diabetic rats (p<0.01). Fluvastatin significantly inhibited NF-kappaB expression and reduced proteinuria (p<0.01). High glucose stimulated the DNA-binding activity of NF-kappaB and phosphorylation of p38MAPK in cultured NRK-52E cells (p<0.01). This stimulatory effect of high glucose on NF-kappaB was blocked by SB203580. Incubation of cells with fluvastatin significantly inhibited the high glucose-induced NF-kappaB activation in a dose-dependent (10-7 to 10-5 mol/L) manner (p<0.05). Exogenous mevalonate (10-4 mol/L) prevented the effect of fluvastatin on NF-kappaB activation.


CONCLUSIONS
These results suggest that fluvastatin reduces high glucose-induced NF-kappaB activation via the p38MAPK pathway in renal tubular epithelial cells in vivo and in vitro. The effect is at least partly due to blocking the biosynthesis of mevalonate.
Department of Nephrology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, PR China. gp6680@sina.com
Ping
P
Gao
Xiaoyan
X
Wu
Hua
H
Shui
Ruhan
R
Jia
D000118:Acetylglucosaminidase / Q000652:urine; D000419:Albuminuria / Q000097:blood / Q000209:etiology / Q000517:prevention & control; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001786:Blood Glucose / Q000378:metabolism*; D015153:Blotting, Western; D002460:Cell Line; D002784:Cholesterol / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D003928:Diabetic Nephropathies / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005260:Female; D000077340:Fluvastatin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology*; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism; D008798:Mevalonic Acid / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009392:Nephrectomy; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014280:Triglycerides / Q000097:blood; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D015415:Biomarkers; D001786:Blood Glucose; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D014280:Triglycerides; D000077340:Fluvastatin; D002784:Cholesterol; D048051:p38 Mitogen-Activated Protein Kinases; D000118:Acetylglucosaminidase; D008798:Mevalonic Acid