Zhong Qing, Sun Feng, Wang Weiguang, Xiao Wenqing, Zhao Xiaoni, Gu Kangding
MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.
MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.
Toxicol Lett. 2017 May 5;273:86-96. doi: 10.1016/j.toxlet.2017.03.019. Epub 2017 Mar 19.
Microcystins (MCs) are a group of monocyclic heptapeptide toxins that have been shown to act as potent hepatotoxins. However, the observed symptoms of water metabolism disruption induced by microcystin-RR (MC-RR) or MCs have rarely been reported, and a relatively clear mechanism has not been identified. In the present study, male mice were divided into 4 groups (A: 140μg/kg, B: 70μg/kg,C: 35μg/kg, and D: 0μg/kg) and administered MC-RR daily for a month. On day 8 of treatment, an increase in water intake and urine output was observed in the high-dose group compared with the control, and the symptoms worsened with the repeated administration of the toxin until day 30. In addition, the urine specific gravity decreased and serum enzymes that can reflect hepatic damage increased in the high-dose group compared with the control (P<0.05). The mRNA level of angiotensinogen (AGT) in hepatocytes was upregulated to approximately 150% of the control (P<0.05), and the serum renin-angiotensin system (RAS) was activated in the high-dose group; however, signs of renal injury were not observed throughout the experiment. After the toxin treatment was completed, the high levels of the RAS and vasopressin in group A returned to normal levels within 1 week. As expected, the symptoms of polyuria and polydipsia also disappeared. Therefore, we propose that water metabolism dysfunction occurs via RAS activation caused by liver damage because the increased serum RAS levels in the experiment were consistent with the increased urine output and water intake in the mice during the observation period. In addition, we found for the first time that a RAS blocker could alleviate the observed polyuria and polydipsia and inactivate the high level of the RAS induced by MC-RR in a dose-dependent manner, which further supported our hypothesis.
微囊藻毒素（MCs）是一类单环七肽毒素，已被证明是强效肝毒素。然而，由微囊藻毒素-RR（MC-RR）或微囊藻毒素引起的水代谢紊乱的观察症状鲜有报道，且尚未确定相对明确的机制。在本研究中，将雄性小鼠分为4组（A组：140μg/kg，B组：70μg/kg，C组：35μg/kg，D组：0μg/kg），每天给予MC-RR，持续一个月。在治疗第8天，与对照组相比，高剂量组的饮水量和尿量增加，随着毒素的反复给药，症状持续恶化直至第30天。此外，与对照组相比，高剂量组的尿比重降低，反映肝损伤的血清酶升高（P<0.05）。肝细胞中血管紧张素原（AGT）的mRNA水平上调至对照组的约150%（P<0.05），高剂量组血清肾素-血管紧张素系统（RAS）被激活；然而，在整个实验过程中未观察到肾损伤迹象。毒素治疗完成后，A组中高水平的RAS和血管加压素在1周内恢复到正常水平。不出所料，多尿和多饮症状也消失了。因此，我们认为水代谢功能障碍是由肝损伤导致的RAS激活引起的，因为实验中血清RAS水平的升高与观察期内小鼠尿量和饮水量的增加一致。此外，我们首次发现RAS阻滞剂可以缓解观察到的多尿和多饮症状，并以剂量依赖的方式使MC-RR诱导的高水平RAS失活，这进一步支持了我们的假设。
