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The Hypertension Induced by Clozapine is Related with Increased Renal Sodium Transporters in Mice
Author(s) -
Ren Zhiyun,
Wang Weiwan,
Zhang Chenyang,
Ye Min,
Wang Xiaoyan
Publication year - 2022
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2022.36.s1.r3489
Subject(s) - clozapine , endocrinology , medicine , pathogenesis , epithelial sodium channel , sodium , chemistry , kidney , nephron , renin–angiotensin system , blood pressure , pharmacology , schizophrenia (object oriented programming) , organic chemistry , psychiatry
Hypertension is caused by multi‐factors, and the pathogenesis is linked to, generally, the increases in the protein expressions and functions of renal sodium transport proteins along the nephron. One of the major side effects of clozapine (common antipsychotic drug) is hypertension. The mechanism is unknown. Hypothesis the pathogenesis of the clozapine‐induced hypertension is associated with increases of renal sodium transport proteins. Methods we examined the blood pressures (BP) and protein expressions of major sodium transport proteins profiled along the renal tubules in the C57Bl6/J male mice (9 weeks old, n=4‐5/group) treated with clozapine at three doses of 5,10 and 20 mg/ kg for 1 week via intraperitoneal injection. Result blood pressures (tail‐cuff, BP98A, softron, Japan) were higher in clozapine at 20mg/kg/day than vehicle (SBP: 130±1.64 vs 109±1.39, DBP: 87 ±4.12 vs 69±2.10 mmHg, n=5/group) and not altered at 5 & 10 mg/kg/day. There were no differences in BW, serum/urine creatinine and electrolytes except for a slight increase in serum sodium at dose of 20 mg/kg (152.8±0.71 vs 150.6±0.40, mmol/L). In renal homogenates, total protein abundance of NaPi2 (western blotting,199±26% of vehicle) NKCC2(184±20), NCC(213±14),and ENaC‐α(217±47),were higher at 20 mg/kg than vehicle. No increases were found in protein expressions of NHE3, αNKA, ENaC‐β and ENaC‐γ. The expressions of renin, AT1R and ACE at 20mg/kg were similar between groups while ACE2 was decreased (42±10). No increases were found in protein expressions of pNKCC2 in 5&10mg/kg(100±50,45±15); NCC was increased at 5 mg/kg (175±9); α NKA was increased in 5mg/kg (216±5) and 10mg/kg (163±2) groups. In plasma membrane enriched fraction (17k), NKCC2(204±43) and ENaC‐α(381±28)were higher at 20 mg/kg than vehicle. In intracellular membrane enriched fraction (200k), NKCC2(521±127) was higher than vehicle. Phosphorylated NKCC2 was increased in renal homogenates(331±35),17k(427±87) 200k(521±127) but WNK4 was not changed. Additional mice were treated with clozapine at 20mg/kg/day via osmotic mini‐pump for 1 week (mini‐pump) or administrated by intraperitoneal injection for 2 weeks (2wks). Increases of renal NKCC2 (mini‐pump:180±21, 2wks:153±18) and NCC (mini‐pump:171±22, 2 wks:160±23) were also found in those models. Conclusions increases of renal sodium transport proteins, mainly pNKCC2 and NKCC2, contribute to the dose‐related increase of BP in mice treated with clozapine and may play an important role in the pathogenesis of the clozapine‐induced hypertension.