Hypercholesterolaemia induces early renal lesions characterized by upregulation of MMP-9 and iNOS and ETAR: alleviated by a dual endothelin receptor antagonist CPU0213 and simvastatin
Lu Luo
Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China
Search for more papers by this authorCorresponding Author
Dr De-Zai Dai
Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China
2Research Division of Pharmacology, China Pharmaceutical University, Nanjing, 210009, China. E-mail: [email protected]Search for more papers by this authorYu-Fen Zheng
Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China
Search for more papers by this authorYin Dai
Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China
Search for more papers by this authorLu Luo
Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China
Search for more papers by this authorCorresponding Author
Dr De-Zai Dai
Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China
2Research Division of Pharmacology, China Pharmaceutical University, Nanjing, 210009, China. E-mail: [email protected]Search for more papers by this authorYu-Fen Zheng
Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China
Search for more papers by this authorYin Dai
Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China
Search for more papers by this authorAbstract
Objectives We aimed to investigate hypercholesterolaemia-induced early renal lesions which result in abnormal expression of endothelin A receptor (ETAR), 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.).
Key findings 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 ETAR, 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 ETAR, 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.
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