Effect of nobiletin on endothelial dysfunction in pregnancy-induced hypertension rats by regulating RhoA/ROCK signaling pathway
Objective To investigate the effect of nobiletin on endothelial dysfunction in pregnancy-induced hyper-tension(PIH)rats by regulating the Ras homolog gene family,member A(RhoA)/Rho associated coiled coil-forming kinase(ROCK)signaling pathway.Methods Pregnant SD rats were prepared from male and female caged rats.The PIH rat model was established by gavage of N-nitro-L-arginine methylester(L-NAME).They were randomly grouped into model group,low dose(3.6 mg/kg)nobiletin group,high dose(7.2 mg/kg)nobiletin group,high dose(7.2 mg/kg)nobiletin+lysophosphatidic acid(LPA)(RhoA/ROCK signal activator,1 mg/kg)group,with 10 pregnant rats in each group,another 10 pregnant mice were given an equal dose of physiological saline by gavage as the control group.After treating with nobiletin and LPA,blood pres-sure of rats in each group was measured.The 24-hour urine protein content of rats in each group was detected,and H-E stain-ing was applied to detect the pathological morphology of their renal and placental tissues.Enzyme linked immunosorbent assay(EL AS A)was applied to detect the levels of serum endothelin 1(ET-1),thromboxane B2(TXB2),nitric oxide(NO),tumor necrosis factor-α(TNF-α),interleukin(IL)-6,and IL-17,the biomarkers of endothelial function in rats of each group.Immunoblotting was applied to detect the expression of RhoA/ROCK pathway related proteins in placental tissue of rats in each group.Results Compared with the control group,the renal and placental morphogenesis of the model group rats suffered severe pathological damage,the systolic blood pressure,diastolic blood pressure,mean arterial pressure,24-hour urine protein content,the levels of serum ET-1,TXB2,TNF-α,IL-6 and IL-17,and the expression of RhoA,ROCK1 and ROCK2 proteins in placental tissue increased(P＜0.05),the level of serum NO decreased(P＜0.05).Compared with the model group,the mor-phological and pathological damages of renal tissue and placental tissue of rats in the low dose nobiletin group and the high dose nobiletin group were alleviated,the systolic blood pressure,diastolic blood pressure,mean arterial pressure,24-hour urine protein content,the levels of serum ET-1,TXB2,TNF-α,IL-6 and IL-17,and the expression of RhoA,ROCK1 and ROCK2 proteins in placental tissue decreased(P＜0.05),the level of serum NO increased(P＜0.05),and high dose Nobiletin has a stronger effect.LPA can weaken the effect of nobiletin on PIH model rats.Conclusion Nobiletin can inhibit the inflam-mation of PIH rats by inhibiting the activation of RhoA/ROCK signal,thereby improving endothelial dysfunction and allevi-ating the damages of kidney and placenta tissue,ultimately alleviating symptoms of hypertension in rats.
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