cpu0213 and Body-Weight

We aimed to investigate hypercholesterolaemia-induced early renal lesions which result in abnormal expression of endothelin A receptor (ET(A)R), induced nitric oxide synthase (iNOS) and matrix metalloproteinase 9 (MMP-9). We hypothesized that this is due to an upregulated endothelin (ET) pathway consequent to hypercholesterolaemia and that CPU0213, a dual ET antagonist, could mitigate these changes.. Rats were randomly divided into four groups: (1), control; (2), high-fat diet for 60 days (HFD); HFD rats medicated in the last 15 days with either (3) CPU0213 (30 mg/kg daily, s.c.) or (4) simvastatin (4 mg/kg daily, p.o.).. Body weight, serum triglycerides, total cholesterol and low-density-lipoprotein cholesterol were significantly increased, whereas high-density lipoprotein cholesterol decreased in the HFD group, relative to normal. Meanwhile, these changes were associated with upregulation of mRNA and protein of ET(A)R, iNOS and MMP-9 in the kidney. The lipid-lowering effect of simvastatin was predominant, lessening abnormal expression of these molecules in the kidney dramatically. Interestingly, CPU0213 significantly normalized expression of mRNA and protein of ET(A)R, iNOS and MMP-9, comparable with simvastatin, leaving no changes in hyperlipidaemia.. CPU0213 relieves renal lesions by blunting hypercholesterolaemia caused by the upregulated ET system, iNOS and MMP-9 in the kidney. This indicates that CPU0213 is promising in treating patients with end stage renal disease.

Topics: Animals; Body Weight; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Endothelin A Receptor Antagonists; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Kidney; Kidney Diseases; Male; Matrix Metalloproteinase 9; Nitric Oxide Synthase Type II; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; RNA, Messenger; Simvastatin; Triglycerides; Up-Regulation