Protective effects of C-type natriuretic peptide on cisplatin-induced nephrotoxicity in Mice
Protective effects of C-type natriuretic peptide on cisplatin-induced nephrotoxicity in Mice
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DOI：
10.1007/s00280-015-2734-7
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发表时间：
2015-05-01
影响因子：
3
通讯作者：
Kangawa, Kenji
中科院分区：
文献类型：
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作者：
Kimura, Toru;Nojiri, Takashi;Kangawa, Kenji
顺铂是一种用于治疗多种恶性肿瘤的高效化疗药物，但其肾毒性使其有效性受到影响。C型利钠肽(CNP)是利钠肽家族的一员，通过激活其特异性受体鸟苷酸环化酶(GC)-B发挥抗炎作用。已知CNP和GC-B受体在血管内皮细胞和肾脏中都有表达。为探讨环磷酰胺(CNP)对顺铂所致小鼠肾毒性的保护作用，将C57BL/6小鼠随机分为3组：正常对照组、顺铂(20 mg/kg，腹腔注射)组和顺铂(2.5Aµg/kg/min，皮下注射)组。顺铂注射后72h采尿、血、肾标本。对尿样和血样进行生化检查。CNP可减轻顺铂诱导的肾小管损伤和细胞凋亡，并抑制血浆尿素氮和肌酐水平，而顺铂可使其升高。CNP治疗可降低肾脏损伤分子-1和单核细胞趋化蛋白-1的表达，而顺铂可使肾脏损伤分子-1和单核细胞趋化蛋白-1的表达升高。CNP治疗可减轻顺铂所致肾损伤时GC-B表达的降低。本研究首次表明CNP可抑制顺铂所致的肾毒性和肾细胞损伤。其作用机制可能与下调炎症细胞因子在顺铂诱导的肾损伤中的表达及减轻肾小管上皮细胞的凋亡有关。
Cisplatin is a highly effective chemotherapeutic agent used to treat various malignancies, but its utility is compromised by its nephrotoxicity. C-type natriuretic peptide (CNP), a member of the natriuretic peptide family, exhibits anti-inflammatory effects by activating its specific receptor, guanylyl cyclase (GC)-B. CNP and GC-B receptor are known to be expressed in both the vascular endothelium and the kidney. The objective of this study was to investigate the renoprotective effects of CNP in a mouse model of cisplatin-induced nephrotoxicity.C57BL/6 mice were divided into three groups: normal control mice; cisplatin (20 mg/kg, intraperitoneal) mice treated with vehicle; and cisplatin mice treated with CNP (2.5 A mu g/kg/min, subcutaneous). At 72 h after cisplatin injection, urine, blood and kidney samples were collected. Urine and blood samples were examined biochemically. Histological findings and gene expression in kidney tissue were evaluated.CNP reduced histological renal tubular damage and apoptosis induced by cisplatin and suppressed plasma blood urea nitrogen and creatinine levels, which were elevated by cisplatin administration. CNP treatment decreased the expression of kidney injury molecule-1 and monocyte chemoattractant protein-1, which were elevated in the kidney by cisplatin administration. CNP treatment attenuated the decrease in GC-B expression in cisplatin-induced kidney injury.The present study is the first to show that CNP inhibits nephrotoxicity and kidney cell damage induced by cisplatin. The mechanism of action may involve down-regulation of inflammatory cytokine expression in cisplatin-induced kidney injury and attenuation of apoptosis in renal tubular cells.