螺内酯调控Hippo-YAP/TAZ信号通路对自发性高血压大鼠肾纤维化及炎症的影响OA

Objective:To investigate the role of spironolactone in alleviating renal fibrosis and inflamma-tory responses in SHR rats by modulating the Hippo-Yes-associated protein(Hippo-YAP)/transcription co-activator with PDZ-like domain(TAZ)signalling pathway.Methods:Eleven specific pathogen-free 8-week-old male Wistar-Kyoto rats were selected as the control group.Forty-four SHR rats were randomly divided in-to 4 groups,including the model group,the low-dose spironolactone group,the high-dose spironolactone group,and the enalapril(ENA)group,with 11 rats in each group.The control and model groups were ad-ministered saline(10mL/kg)daily by gavage;the low-dose spironolactone group received spironolactone(10mg/kg)daily by gavage(diluted in saline to 10mL/kg);the high-dose spironolactone group received spironolactone(20mg/kg)daily by gavage(diluted in saline to 10mL/kg);the enalapril group was given en-alapril(10mg/kg)daily by gavage(diluted in saline to 10mL/kg).After 20 weeks of intervention,non-in-vasive tail-cuff blood pressure monitoring was used weekly to measure systolic blood pressure(SBP)and dias-tolic blood pressure(DBP).At the end of the intervention,blood was collected from the abdominal aorta,centrifuged to separate serum,and creatinine(Cr)and urea nitrogen(BUN)levels were measured enzymati-cally.Rats were euthanized to collect kidney tissues,and Western blot was used to assess the expression of transforming growth factor-beta1(TGF-β1),alpha-smooth muscle actin(α-SMA),YAP,TAZ,and phos-phorylated YAP(p-YAP)proteins;immunohistochemical staining was used to detect the positive rate of typeⅢ collagen(Col Ⅲ);Masson's trichrome staining was used to evaluate the area of renal fibrosis;and enzyme-linked immunosorbent assay(ELISA)was used to measure serum levels of Interleukin-2(IL-2),interleu-kin-8(IL-8),interleukin-17A(IL-17A).Results:Compared to the control group,the model group showed significant increases in SBP,DBP,serum Cr,BUN levels,renal tissue expression of TGF-β1,α-SMA,YAP,TAZ,Col Ⅲ positivity rate,fibrosis area,and significant increases in serum IL-2,IL-8,IL-17A levels,with a significant decrease in p-YAP expression(all P<0.05).Compared to the model group,the low-dose spironolactone,high-dose spironolactone,and enalapril groups showed significant improvements in the above indicators(all P<0.05),with the high-dose spironolactone group showing better improvement than the low-dose group(all P<0.05).Conclusion:Spironolactone can dose-dependently reduce blood pressure in SHRs and alleviate renal fibrosis and inflammation,a mechanism associated with the inhibition of Hippo-YAP/TAZ signaling pathway activation.