title: Hypercholesterolaemia induces early renal lesions characterized by upregulation of MMP-9 and iNOS and ET(A)R: alleviated by a dual endothelin receptor antagonist CPU0213 and simvastatin.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Luo
authors.forename: Yu-Fen
authors.initials: YF
authors.lastname: Zheng
authors.forename: Yin
authors.initials: Y
authors.lastname: Dai
authors.forename: De-Zai
authors.initials: DZ
authors.lastname: Dai
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D065130:Endothelin A Receptor Antagonists; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy*; D007668:Kidney / Q000378:metabolism; D007674:Kidney Diseases / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000096:biosynthesis* / Q000235:genetics; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D014280:Triglycerides / Q000097:blood; D015854:Up-Regulation
chemical_list: C513821:CPU0213; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D065130:Endothelin A Receptor Antagonists; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011720:Pyrazoles; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D014280:Triglycerides; D002784:Cholesterol; D019821:Simvastatin; D052247:Nitric Oxide Synthase Type II; D020780:Matrix Metalloproteinase 9