Ezetimibe Ameliorates Early Diabetic Nephropathy in db/db Mice

Abstract

Aim: Lipid-lowering medications have been suggested to have a potential benefit in the treatment of chronic kidney disease (CKD) such as diabetic nephropathy. Although ezetimibe has been widely used to lower serum cholesterol levels, the effect of this drug on diabetic nephropathy remains unclear. In the present study, therefore, we examined the protective effect of ezetimibe on diabetic nephropathy in db/db mice. Method: Db/db mice were fed a standard diet with 0.01% (w/w) of ezetimibe for 8 weeks from 8 weeks of age. Results: Treatment with ezetimibe did not affect food intake, body weight gain, adiposity, or blood pressure in db/db mice. Ezetimibe also had no effect on glucose metabolism such as fasting plasma glucose and insulin; however, it markedly reduced plasma lipid levels and hepatic lipid contents and reduced the urinary excretion of albumin by 50% in db/db mice, suggesting the effect of ezetimibe on diabetic nephropathy. Furthermore, ezetimibe improved glomerular hypertrophy. Although ezetimibe had no effect on oxidative stress measured by urinary 8-OHdG in db/db mice, the plasma adiponectin level was normalized, and the expression of adiponectin receptor 1 in the kidney was increased by ezetimibe treatment. Conclusion: Our data suggest that ezetimibe can improve early diabetic nephropathy through its hypolipidemic effect, and the amelioration of adiponectin resistance may also be responsible for the renoprotective effect of ezetimibe as its underlying mechanism. J Atheroscler Thromb, 2012; 19:608-618.

Deletion of the gene for adiponectin accelerates diabetic nephropathy in the Ins2 +/C96Y mouse

“…These results are consistent with previous findings of adiponectin receptor expression patterns in tissues and in kidney cell culture [12,17,20]. Interestingly, in studies using streptozotocin-induced diabetic rats and type 2 diabetic db/ db mice, the expression of adipoR1 mRNA and protein was decreased in whole renal cortical tissue [27,28]. These differences may be a consequence of the specific disease models but also suggest that adipoR1 expression may be regulated differentially in the glomerular and tubulointerstitial compartments of the kidney.…”

Inflammation in Diabetic Nephropathy

“…Adiponectin may also interfere with receptor activation for platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and epidermal growth factor (EGF) [95]. In diabetic db/db mice, ezetimibe treatment normalized adiponectin levels and enhanced kidney expression of adiponectin receptor 1 [96]. With this, there was a 50% reduction in albuminuria and improved glomerular hypertrophy.…”

Effects of short‐term add‐on ezetimibe to statin treatment on expression of adipokines and inflammatory markers in diabetic and dyslipidemic patients

“…suggesting that ezetimibe has a nephroprotective effect that is modulated by this adipokine receptor. 31 We also evaluated the mRNA and protein expression of resistin, a hormone with proinflammatory activity that has also been associated with insulin resistance. Mounting evidence indicates that resistin plays important regulatory roles, apart from its function in insulin resistance and diabetes, in a variety of biological processes including atherosclerosis and CVD.…”