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目的探讨FK506对早期糖尿病肾病大鼠肾小球足细胞损伤的保护作用。方法将38只正常雄性SD大鼠随机分为正常对照组(N组)8只、糖尿病肾病组(DN组)10只、FK506治疗组(F组)10只、洛汀新治疗组(L组)10只,其中DN组、F组、L组应用链脲佐菌素(STZ)60 mg/kg腹腔注射建立糖尿病大鼠模型。F组成模4周后给予FK506 1 mg/(kg.d)灌胃,L组成模4周后给予洛汀新10 mg/(kg.d)灌胃,DN组与N组4周后给予等量蒸馏水灌胃,每4周末监测各组大鼠血糖(BS)、体质量(BW)、24 h尿蛋白定量,药物干预8周后测定各组大鼠的血肌酐(SCr)、尿素氮(BUN)、肾质量/体质量(KW/BW),在光镜、电镜下观察肾脏病理组织学改变,应用West-ern blot印迹检测足细胞特异标记物Nephrin的蛋白表达。结果①与N组比较,DN组大鼠BS、SCr、BUN、KW/BW、24 h尿蛋白定量均明显上升(P<0.05);与DN组比较,F组和L组上述指标除BS外均明显降低(P<0.05),且F组和L组之间差异无统计学意义(P>0.05);②光镜下,肾组织病理学观察N组无明显异常,DN组可见明显的肾小球体积增大,肾小球系膜细胞增生,系膜区增宽,基底膜增厚;F组、L组较DN组病理改变明显减轻(P<0.05),且F组和L组之间病理改变无显著性差异(P>0.05);③电镜下,DN组肾小球基底膜显著增宽,足突排列紊乱,足突增宽、融合,F组、L组较DN组上述病变有所减轻(P<0.05);④Western blot结果显示,DN组肾组织Nephrin蛋白表达较N组下降60.1%(P<0.05),F组和L组可明显恢复肾组织Nephrin蛋白的表达(P<0.05)。结论 FK506可能部分通过恢复糖尿病大鼠肾组织Nephrin蛋白表达、维护足细胞结构和功能的完整而发挥减少尿蛋白、延缓DN进展的作用。
Objective To investigate the protective effect of FK506 on glomerular podocyte injury in early diabetic nephropathy rats. Methods Thirty-eight male Sprague Dawley rats were randomly divided into normal control group (n = 8), diabetic nephropathy group (n = 10), FK506 treatment group (group F) ). Ten rats in DN group, F group and L group were treated with streptozotocin (STZ) 60 mg / kg intraperitoneally to establish diabetic rat model. Four weeks later, F group was given FK506 1 mg / (kg · d) orally. L model was given to Lotensin 10 mg / (kg · d) orally after 4 weeks, DN group and N group were given four weeks later (BS), body weight (BW) and 24-hour urinary protein were measured every 4 weeks. Serum creatinine (SCr) and urea nitrogen BUN and KW / BW. The renal histopathological changes were observed under light microscope and electron microscope. The protein expression of podocyte specific marker Nephrin was detected by West-ern blot. Results ①Compared with N group, the urinary protein of BS, SCr, BUN, KW / BW and 24 h in DN group increased obviously (P <0.05). Compared with DN group, (P <0.05), and there was no significant difference between F group and L group (P> 0.05). ② Under light microscope, there was no significant abnormality in pathological observation of N group The volume of globules increased, mesangial cells proliferated, the mesangial area was broadened, and the basement membrane was thickened. The pathological changes in group F and group L were significantly relieved (P <0.05), and those in group F and L (P> 0.05). ③ Under electron microscope, the glomerular basement membrane in DN group was significantly broadened, foot processes arranged disorderly, foot process widened, fusion, and the above lesions in group F and group L (P <0.05). ④Western blot results showed that Nephrin protein expression in DN group was decreased by 60.1% (P <0.05) compared with that in N group. Nephrin protein expression in renal tissues was significantly restored in group F and L (P < 0.05). Conclusion FK506 may play a role in reducing proteinuria and delaying the progression of DN partly by restoring the expression of Nephrin protein in renal tissue of diabetic rats and maintaining the integrity of podocyte structure and function.