摘要目的 探讨有氧运动对自发性高血压大鼠(SHR)肾脏纤维化的影响并探讨肾小管上皮－间质转化(EMT)在其间的作用机制。方法 将10只Wistar-Kyoto大鼠作为正常血压对照组(WKY),30只雄性SHR按照随机数字表法分为高血压安静组(SHR-S)和高血压运动组(SHR-E),每组15只。WKY和SHR-S组在鼠笼内安静饲养,SHR-E组进行8周跑台运动。实验后,利用无创血压仪检测尾动脉血压;测定24 h尿蛋白(UP)、血尿素氮(BUN)和血清肌酐(SCr)含量评价肾功能;Masson染色进行肾脏病理组织学观察并获取纤维化指数(FI);免疫印迹测定转化生长因子β1(TGF-β1)、磷酸化Smad2/3(p-Smad2/3)、α-平滑肌肌动蛋白(α-SMA)和E-钙黏蛋白(E-CA)表达量。结果 与WKY组比较,SHR-S组血压[SBP:(177.3±17.2) mmHg vs. (110.6±13.3)mmHg,P<0.05;DBP:(108.1±6.3) mmHg vs. (75.6±4.9) mmHg,P<0.05;MAP:(131.1±7.4) mmHg vs. (87.3±4.7) mmHg,P<0.05]、肾脏FI[(7.87±1.89)% vs. (0.43±0.05)%,P<0.05]、UP[(197.3±41.6) mg/24 h vs. (89.2±9.5) mg/24 h,P<0.05]、BUN[(14.3±2.9) mmol/L vs. (4.9±1.0) mmol/L,P<0.05]和SCr[(98.6±10.1) μmol/L vs. (35.8±4.3) μmol/L,P<0.05]升高,TGF-β1、p-Smad2、p-Smad3和α-SMA蛋白表达上调(P<0.05),E-CA蛋白表达下调(P<0.05);与SHR-S组比较,SHR-E组血压[SBP:(152.3±14.2) mmHg vs. (177.3±17.2) mmHg,P<0.05;DBP:(93.1±9.7) mmHg vs. (108.1±6.3) mmHg,P<0.05;MAP:(112.8±7.9) mmHg vs. (131.1±7.4) mmHg,P<0.05]、肾脏FI[(3.02±0.91)% vs. (7.87±1.89)%,P<0.05]、UP[(127.9±25.7)mg/24 h vs. (197.3±41.6) mg/24 h,P<0.05]、BUN[(6.8±1.7) mmol/L vs. (14.3±2.9) mmol/L,P<0.05]和SCr[(50.3±6.0) μmol/L vs. (98.6±10.1) μmol/L,P<0.05]下降,TGF-β1、p-Smad2、p-Smad3和α-SMA蛋白表达下调(P<0.05),E-CA蛋白表达上调(P<0.05)。结论 有氧运动可能通过调控TGF-β1/Smad信号途径抑制高血压肾病大鼠肾小管EMT,进而改善肾脏纤维化并提高肾功能。
Abstract：Objective To explore the effect of aerobic exercise on renal fibrosis in spontaneously hypertensive rats (SHRs) and investigate the mechanism of renal tubular epithelial-interstitial transformation (EMT) in the above process so as to facilitate targeted exercise prescriptions for patients with hypertensive nephropathy.Methods Ten Wistar-Kyoto rats were used as the normal blood pressure control group (WKY),while another 30 male SHRs were randomly divided into the hypertensive sedentary group (SHR-S) and hypertensive exercise group (SHR-E).The rats in WKY and SHR-S groups were reared quietly in cages,while those in the SHR-E group were trained on a treadmill for 8 weeks.After the experiment,caudal artery blood pressure was measured by a non-invasive sphygmomanometer while 24-hour urinary protein (UP),blood urea nitrogen (BUN) and serum creatinine (SCr) were measured to evaluate renal function.Renal histopathology was observed with Masson staining and the fibrosis index (FI) was obtained.The expressions of transforming growth factor-β1 (TGF-β1),phosphorylated Smad2/3 (p-Smad2/3),α-smooth muscle actin (α-SMA) and E-cadherin (E-CA) were determined by Western Blotting.Results Compared with the WKY group,blood pressure [SBP:(177.3±17.2) mmHg vs. (110.6±13.3) mmHg,P<0.05;DBP:(108.1±6.3) mmHg vs.(75.6±4.9) mmHg,P<0.05;MAP:(131.1±7.4) mmHg vs. (87.3±4.7) mmHg,P<0.05],renal FI[(7.87±1.89)% vs.(0.43±0.05)%,P<0.05],UP[(197.3±41.6) mg/24 h vs.(89.2±9.5) mg/24 h,P<0.05],BUN [(14.3±2.9) mmol/L vs. (4.9±1.0) mmol/L,P<0.05] and SCr [(98.6±10.1) μmol/L vs. (35.8±4.3) μmol/L,P<0.05] increased,TGF-β1,p-Smad2,p-Smad3 and α-SMA protein expression up-regulated (P<0.05) while E-CA protein expression down-regulated (P<0.05) in SHR-S group.Compared with SHR-S group,blood pressure [SBP:(152.3±14.2) mmHg vs. (177.3±17.2) mmHg,P<0.05;DBP:(93.1±9.7) mmHg vs. (108.1±6.3) mmHg,P<0.05;MAP:(112.8±7.9) mmHg vs. (131.1±7.4) mmHg,P<0.05],renal FI[(3.02±0.91)% vs. (7.87±1.89)%,P<0.05],UP[(127.9±25.7) mg/24 h vs. (197.3±41.6) mg/24 h.P<0.05],BUN [(6.8±1.7) mmol/L vs. (14.3±2.9) mmol/L,P<0.05] and SCr [(50.3±6.0) μmol/L vs. (98.6±10.1) μmol/L,P<0.05] decreased,TGF-β1,p-Smad2 p-Smad3 and α-SMA protein expressions down-regulated (P<0.05) and E-CA protein expression up-regulated (P<0.05) in SHR-E group.Conclusions Aerobic exercise may improve renal fibrosis by inhibiting renal tubular EMT via regulation of TGF-β1/Smad signal pathway,thus enhancing renal function in rats with hypertensive nephropathy.
Mills K T,Stefanescu A,He J.The global epidemiology of hypertension[J].Nat Rev Nephrol,2020,16(4):223-237.
[2]
Sun H J.Current opinion for hypertension in renal fibrosis[J].Adv Exp Med Biol,2019,1165:37-47.
[3]
Hu H H,Chen D Q,Wang Y N,et al.New insights into TGF-β/Smad signaling in tissue fibrosis[J].Chem Biol Interact,2018,292:76-83.
[4]
Jin J,Gong J,Zhao L,et al.Inhibition of high mobility group box 1 (HMGB1) attenuates podocyte apoptosis and epithelial-mesenchymal transition by regulating autophagy flux[J].J Diabetes,2019,11(10):826-836.
[5]
Igarashi Y,Nogami Y.The effect of regular aquatic exercise on blood pressure:a meta-analysis of randomized controlled trials[J].Eur J Prev Cardiol,2018,25(2):190-199.
Sallis R E.Exercise in the treatment of chronic disease:an underfilled prescription[J].Curr Sports Med Rep,2017,16(4):225-226.
[9]
Peng C C,Chen K C,Hsieh C L,et al.Swimming exercise prevents fibrogenesis in chronic kidney disease by inhibiting the myofibroblast transdifferentiation[J].PLoS One,2012,7(6):e37388.
[10]
Moraes M R,Rosa T S,Souza M K,et al.Resistance training downregulates macrophages infiltration in the kidney of 5/6 nephrectomized rats[J].Life Sci,2018,213:190-197.
[11]
Ma T T,Meng X M.TGF-β/Smad and renal fibrosis[J].Adv Exp Med Biol,2019,1165:347-364.
[12]
Hills C E,Squires P E.The role of TGF-β and epithelial-to mesenchymal transition in diabetic nephropathy[J].Cytokine Growth Factor Rev,2011,22(3):131-139.
[13]
Zhang Y,Li H,Zhu J,et al.Role of artesunate in TGF-β1 induced renal tubular epithelial mesenchymal transdifferentiation in NRK-52E cells[J].Mol Med Rep,2017,16(6):8891-8899.
[14]
Morizane R,Fujii S,Monkawa T,et al.miR-363 induces transdifferentiation of human kidney tubular cells to mesenchymal phenotype[J].Clin Exp Nephrol,2016,20(3):394-401.
[15]
Gu L,Gao Q,Ni L,et al.Fasudil inhibits epithelial-myofibroblast transdifferentiation of human renal tubular epithelial HK-2 cells induced by high glucose[J].Chem Pharm Bull (Tokyo),2013,61(7):688-694.
2021, Vol. 32 
