Ueda Miki, Uchimura Kohei, Narita Yuki, Miyasato Yoshikazu, Mizumoto Teruhiko, Morinaga Jun, Hayata Manabu, Kakizoe Yutaka, Adachi Masataka, Miyoshi Taku, Shiraishi Naoki, Kadowaki Daisuke, Sakai Yoshiki, Mukoyama Masashi, Kitamura Kenichiro
Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
Nephron. 2015;129(3):223-32. doi: 10.1159/000375308. Epub 2015 Mar 3.
BACKGROUND/AIMS: We have so far demonstrated the renoprotective effect of camostat mesilate (CM) in 5/6 nephrectomized rats at least partly through its antioxidant effect. However, precise mechanisms were not fully clarified. Therefore, we now examined the renoprotective and antioxidant mechanisms of CM by using the adenine-induced chronic kidney disease (CKD) rat model.
In protocol 1, we analyzed the effect of CM on CKD. Rats were fed on a 0.75% adenine diet for 3 weeks to induce CKD followed by the experimental period with vehicle, CM, or hydralazine (HYD) treatment for 5 weeks. In protocol 2, we examined the safety of CM and HYD on the normal rats. In addition, we explored free radical scavenging activities of CM and its metabolites in vitro using electron paramagnetic resonance (EPR) spectroscopy.
CM, but not HYD, significantly reduced the serum creatinine levels, although both treatments showed similar reduction in the blood pressure. CM decreased mRNA expression and protein levels of fibrotic markers, the severity of renal fibrosis, the accumulation of oxidative stress, and the expression of NADPH oxidase components in the kidney. In the protocol 2, there were no statistically significant differences in general parameters except for the systolic blood pressure in HYD group. EPR study revealed that CM and its metabolites have potent hydroxyl radical scavenging activities in vitro.
Our findings indicate that CM significantly ameliorates the progression of CKD partly through its antioxidant effect independently from its blood pressure-lowering effect. Our results suggest the possibility that CM could be a new therapeutic agent that could arrest the progression of CKD.
背景/目的：我们此前已证明甲磺酸加贝酯（CM）对5/6肾切除大鼠具有肾脏保护作用，至少部分是通过其抗氧化作用实现的。然而，确切机制尚未完全阐明。因此，我们现在使用腺嘌呤诱导的慢性肾脏病（CKD）大鼠模型来研究CM的肾脏保护和抗氧化机制。
在方案1中，我们分析了CM对CKD的影响。大鼠喂食0.75%腺嘌呤饮食3周以诱导CKD，随后在实验期分别用赋形剂、CM或肼屈嗪（HYD）处理5周。在方案2中，我们研究了CM和HYD对正常大鼠的安全性。此外，我们使用电子顺磁共振（EPR）光谱在体外探索了CM及其代谢产物的自由基清除活性。
CM能显著降低血清肌酐水平，而HYD则不能，尽管两种处理在血压降低方面表现相似。CM降低了纤维化标志物的mRNA表达和蛋白水平、肾纤维化的严重程度、氧化应激的积累以及肾脏中NADPH氧化酶成分的表达。在方案2中，除HYD组的收缩压外，一般参数无统计学显著差异。EPR研究表明，CM及其代谢产物在体外具有强大的羟基自由基清除活性。
我们的研究结果表明，CM可部分通过其抗氧化作用而非降压作用显著改善CKD的进展。我们的结果提示CM有可能成为一种能够阻止CKD进展的新型治疗药物。
