Honma Shigeyoshi, Shinohara Masahiro, Takahashi Naho, Nakamura Kazuki, Hamano Shohei, Mitazaki Satoru, Abe Sumiko, Yoshida Makoto
Department of Pharmacology, Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki 370-0033, Gunma, Japan.
Department of Pharmacology, Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki 370-0033, Gunma, Japan.
Eur J Pharmacol. 2014 Oct 5;740:578-83. doi: 10.1016/j.ejphar.2014.06.027. Epub 2014 Jun 26.
Unilateral ureteral obstruction (UUO) is a well-established model for the study of interstitial fibrosis in the kidney. In this study, we investigated the effects of a COX-2 inhibitor, meloxicam, on UUO-induced renal interstitial fibrosis in mice. Serum creatinine, blood urea nitrogen and urinary glucose were significantly increased by UUO. However, all of these changes were attenuated by meloxicam (1 mg/kg/day). Masson׳s trichrome staining showed that interstitial fibrosis was significantly increased by UUO, but that meloxicam also significantly diminished the area of UUO-induced fibrosis. Heat shock protein (HSP) 47 protein, a collagen-specific molecular chaperone essential for the biosynthesis of collagen molecules, and type IV collagen mRNA were increased in kidneys of UUO mice. Meloxicam reduced the expression of both HSP47 protein and type IV collagen mRNA. The phosphorylation of extracellular regulated kinase (ERK) and c-jun-N-terminal kinase (JNK) was increased by UUO, but these changes were inhibited by meloxicam. Collectively, these results suggest that COX-2 may be involved in the expression of HSP47 and type IV collagen through the phosphorylation of ERK and JNK, accelerating renal interstitial fibrosis.
单侧输尿管梗阻（UUO）是研究肾脏间质纤维化的一种成熟模型。在本研究中，我们调查了环氧化酶-2（COX-2）抑制剂美洛昔康对UUO诱导的小鼠肾间质纤维化的影响。UUO使血清肌酐、血尿素氮和尿葡萄糖显著升高。然而，美洛昔康（1毫克/千克/天）可减轻所有这些变化。Masson三色染色显示，UUO使间质纤维化显著增加，但美洛昔康也显著减小了UUO诱导的纤维化面积。热休克蛋白（HSP）47蛋白是胶原分子生物合成所必需的一种胶原特异性分子伴侣，在UUO小鼠的肾脏中，HSP47蛋白和IV型胶原mRNA增加。美洛昔康降低了HSP47蛋白和IV型胶原mRNA的表达。UUO使细胞外调节激酶（ERK）和c-jun氨基末端激酶（JNK）的磷酸化增加，但这些变化被美洛昔康抑制。总体而言，这些结果表明，COX-2可能通过ERK和JNK的磷酸化参与HSP47和IV型胶原的表达，从而加速肾间质纤维化。
