Water metabolism dysfunction via renin-angiotensin system activation caused by liver damage in mice treated with microcystin-RR.
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.
MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.
Qing
Q
Zhong
MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.
Feng
F
Sun
MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.
Weiguang
W
Wang
MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.
Wenqing
W
Xiao
MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.
Xiaoni
X
Zhao
MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China. Electronic address: hygkd@mails.tjmu.edu.cn.
Kangding
K
Gu
D000577:Amides / Q000494:pharmacology; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism* / Q000652:urine; D004305:Dose-Response Relationship, Drug; D005650:Fumarates / Q000494:pharmacology; D008297:Male; D008387:Marine Toxins; D008815:Mice, Inbred Strains; D052998:Microcystins / Q000633:toxicity*; D059606:Polydipsia / Q000139:chemically induced / Q000378:metabolism; D011141:Polyuria / Q000139:chemically induced / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects*; D014867:Water / Q000378:metabolism*; D014874:Water Pollutants, Chemical / Q000633:toxicity*
D000577:Amides; D005650:Fumarates; D008387:Marine Toxins; D052998:Microcystins; D014874:Water Pollutants, Chemical; D014867:Water; C446481:aliskiren; C063855:microcystin RR
Aliskiren; Liver damage; Microcystin-RR; Polydipsia; Polyuria; Renin-angiotensin system