摘要
背景:
糖尿病肾病(Diabetic nephropathy，DN)是糖尿病微血管的严重并发症之一，目前已逐渐成为导致终末期肾病(ESRD)的主要原因。在欧美等发达国家DN是ESRD的首位原因（30%~40%），在中国为第二位，且有逐渐增多趋势。DN的发病机制至今并不十分清楚，近年来炎症学说倍受关注，并认为DN是一种代谢紊乱诱导的炎症性疾病，其中巨噬细胞浸润是DN炎症的特征性表现之一，也是DN发生、发展的中心环节。而DN时蛋白尿的形成与肾组织内炎症及肾小球滤过屏障通透性改变密切相关。足细胞位于滤过屏障的外层，其损伤参与了蛋白尿形成等DN早期病理进程。DN的显著特征是基质蛋白的聚积最终导致肾小球硬化和间质纤维化，以往很多研究集中在肾小球病变上，但肾小管病变及肾小管-间质纤维化在DN中的重要作用逐渐被大家所认识。肾小管-间质病变是DN进展的主要病理基础之一，是影响DN预后的十分重要的因素。肾小管上皮细胞肌成纤维细胞转分化(tubular epithelial myofibroblast transdifferentiation, TEMT)可能是DN中肾小管间质纤维化的关键环节。但是处于静息或非活化状态的巨噬细胞并无损伤作用，只有被激活的巨噬细胞才能有效发挥其炎症效应。Toll样受体家族（TLRs）正是参与免疫炎症反应的一个关键因素，且认为是介导免疫和炎症反应的主体。他克莫司(tacromulis)即FK506是一种钙神经蛋白（Calcineurin，CaN）抑制剂，目前已被用于多种肾脏疾病（如肾移植术后、狼疮性肾炎、难治性肾病综合征）的治疗，具有肾脏保护作用。有报道指出FK506发挥抑制免疫、抗炎活性可能与抑制CaN、骨桥蛋白(Ostepontin，OPN)、NF-κB等多种炎性细胞因子的表达有关。
目的：
(1)本研究中，通过建立链脲佐菌素(streptozotocin，STZ)诱导的糖尿病大鼠模型，使用FK506干预，探讨其对糖尿病大鼠肾脏保护作用及可能分子机制;(2)探讨FK506是否通过足细胞的保护作用减轻DN大鼠尿白蛋白排泄，并探讨其可能机制;(3)探讨FK506对DM大鼠肾小管-间质损伤的保护作用，并探讨其机制；(4)探讨FK506对DM大鼠肾脏保护作用的机制与肾脏内巨噬细胞浸润、增殖及活化的关系，以及探讨其可能机制。
方法：
40只大鼠随机分为对照组（C）、模型组（DM）、DM+FK5060.5mg/kg d给药组（FK5060.5）及DM+FK5061.0mg/kg d给药组（FK5061.0），每组10只。采用STZ腹腔内注射制造糖尿病大鼠模型。FK506给药组按0.5、1.0mg/kg d灌胃，对照组和模型组每日给予等量溶媒，共4周。4周后大鼠血糖、肝功能、肾功能与血脂由全自动生化分析仪测定，24小时尿白蛋白测定采用酶联免疫方法（EnzymeImmunoassay，EIA）。观察大鼠肾重/体重、尿白蛋白排泄率(AER)与肌酐清除率(Ccr)变化，在光镜、电镜下观察肾脏病理组织学改变。应用免疫荧光检测肾组织Nephrin和Podocin表达情况。并应用免疫组化单染及双染技术检测各组大鼠肾组织骨桥蛋白(OPN)，转化生长因子β1(TGFβ1)，E-钙黏蛋白(E-cadherin)，波形蛋白(Vimentin)，巨噬细胞浸润（单核/巨噬细胞表面特异性标志抗原ED-1+细胞），增殖细胞核抗原(Proliferating cell nuclear antigen, PCNA巨噬细胞增殖指标)，TLR2，TLR4，核转录因子-κB（NF-κB-p-p65）,诱生性一氧化氮合酶（Inducible nitricoxide synthase, iNOS巨噬细胞活化指标）表达情况。应用Western印迹检测CaN、1α(IV)型胶原、α-平滑肌肌动蛋白(α-SMA)、Nephrin、Podocin、NF-κB-p65及NF-κB-p-p65蛋白表达。
结果：
1.各组大鼠生化指标变化与C组相比，DM组大鼠表现为血糖升高、体重下降、相对肾重(肾重/体重)增加(P<0.01)，FK5060.5与1.0mg/kg给药4wk没有防止大鼠血糖升高、体重下降。FK5060.5mg/kg给药组相对肾重较糖尿病组有所下降，但未达统计学意义，FK5061.0mg/kg给药组相对肾重明显低于模型组(P<0.05)。DM组大鼠AER明显高于对照组(P<0.01)，FK5060.5与1.0mg/kg给药组大鼠AER水平明显低于模型组(P<0.05,0.01)。FK5060.5与1.0mg/kg给药组大鼠Ccr水平与DM组相比，差异无统计学意义。DM组大鼠血TC、TG水平明显高于对照组(P<0.05)，FK5060.5与1.0mg/kg给药组血TC、TG水平与模型组相比无明显差异。另外，与C组相比，DM组、各给药组血谷丙转氨酶、谷草转氨酶无明显变化。
2.肾组织病理形态学变化：DM组4周肾小球平均容量(VG)与损伤指数(Indices for tubulointerstitial injury, TII)明显高于C组(P<0.05,0.01)，提示本模型大鼠已出现肾小球肥大与肾小管-间质损害；FK5060.5mg/kg给药组大鼠VG明显低于DM组(P<0.05), TII较模型组有所下降，但差异未达统计学意义，FK5061.0mg/kg给药组VG与TII均明显低于模型组(P<0.05,0.01)。透射电镜观察DM组肾小球基底膜增厚、结构模糊不清，系膜基质增多，足细胞损伤，而与DM组比较，FK5060.5、1.0组肾组织超微结构改变有不同程度改善。
3. FK506对糖尿病大鼠肾脏足细胞损伤的保护作用Western blot法显示DM组肾组织和FK5060.5,1.0组肾组织CaN蛋白表达分别是C组的2.4倍、1.5倍和0.7倍，FK5060.5与1.0组较DM组分别下降38.0%与73.2%；DM组Nephrin和Podocin较C组表达明显下降；FK5060.5,1.0组Nephrin和Podocin量较DM组明显增加，与剂量成正相关。免疫荧光显示Nephrin和Podocin在C组大鼠肾小球呈线状均匀分布，DM组大鼠肾小球表达明显减少、且呈颗粒状不均匀分布;FK5060.5,1.0组Nephrin和Podocin表达不同程度增加，呈线状及颗粒状分布。
4. FK506对糖尿病大鼠肾小管-间质损伤的保护作用C组大鼠肾小球与肾小管-间质有微弱TGFβ1蛋白表达，模型组肾小球与肾小管-间质TGFβ1蛋白表达明显高于C组(P<0.01)，K5060.5与1.0mg/kg给药组肾小球与肾小管-间质TGFβ1蛋白表达明显低于DM组(P<0.05,0.01)。免疫组化显示DM组肾小管-间质E-cadherin表达阳性面积明显低于C组(P<0.01)，FK5060.5、1.0组表达阳性面积明显高于DM组(P<0.01)，DM组肾小管α-SMA与Vimentin表达明显高于对照组(P<0.01)，FK5060.5、1.0组表达明显低于DM组(P<0.01)。Western blot法显示DM组肾组织和FK5060.5,1.0组肾组织α-SMA蛋白表达较C组分别增加3.5倍、2.1倍和1.1倍，FK5060.5,1.0组较DM组分别下降40.7%与69.1%。而DM组、FK5060.5和1.0组肾组织1α(IV)型胶原蛋白表达较C组分别增加2.4倍、1.6倍和1.2倍，FK5060.5,1.0给药组较DM组分别下降34.5%与50.0%。
5. FK506对糖尿病大鼠肾脏巨噬细胞增殖激活的影响免疫组化显示DM组大鼠肾组织ED-1+、PCNA+、TLR2+、TLR4+及iNOS+巨噬细胞数明显高于C组(P<0.01)，FK5060.5,1.0给药组ED-1+的巨噬细胞数与DM组比较无明显变化，PCNA+、TLR2+、TLR4+及iNOS+的巨噬细胞数明显低于DM组(P<0.01)。免疫组化法显示DM组大鼠肾组织NF-κB p-p65蛋白表达明显高于对照组(P<0.01)，而与DM相比，FK5060.5、1.0组肾组织NF-κB p-p65表达明显减少(P<0.01)。Westernblot法显示DM组肾组织NF-κB-p65表达较对照组增加5.33倍，FK5060.5与1.0组肾组织NF-κB-p65表达较DM组分别下降26.32%与47.37%。DM组肾组织NF-κBp-p65表达较对照组增加7.57倍，FK5060.5、1.0组肾组织NF-κB p-p65表达较DM组分别下降56.67%和70.00%。
结论：
FK506能减少糖尿病大鼠尿蛋白排泄，减轻肾小球肥大及肾小管-间质损伤，改善肾小球基底膜、系膜及足细胞病变，其机制可能与下调肾组织中NF-κB p-p65、OPN、CaN、α-SMA、Vimentin、TGFβ1和1α(IV)型胶原的表达，上调E-cadherin、Nephrin和Podocin表达，同时通过下调肾脏巨噬细胞TLR2与TLR4表达，从而抑制TLR-NF-κB信号转导，调节巨噬细胞的增殖与激活，从而对早期糖尿病大鼠肾脏具有保护作用。
Background
Diabetic nephropathy is a serious microvascular complication of diabetes mellitus andthe major cause of chronic renal failure. DN is the first cause of ESRD (30%~40%) inEurope and the United States and other developed countries, second in China, and thereis a potential. The pathogenesis of DN is very complicated and has not been fullyelucidated at present. The theory of inflammation is paid more attention in recent yearsand inflammatory mechanism mainly mediated by macrophages is considered the keyfactor of sustainable development. DN in renal tissue inflammation formation is closelyrelated to the glomerular filtration barrier permeability changes and proteinuria. Theouter layer of podocytes in the filtration barrier, the injury is involved in the formationof protein in the urine DN early pathological process. The typical feature of DN is theaccumulation of matrix protein，which ultimately lead to glomerular sclerosis andinterstitial fibrosis. In the past few years, glomerular disease was focused on. But now，renal tubular lesions and renal tubulointerstitium fibrosis which playing a important roleof DN is gradually known by people. The pathological change of tubulointerstitium isthe main basis of pathology progress in DN. At the same time, it is one of the mostimportant influential factors in the prognosis of DN. Renal tubular epithelialmyofibroblast transdifferentiation (TEMT) maybe the key link in the tubulointerstitiumfibrosis of DN. Non-activated macrophages have no injury effect, only activatingmacrophages can be cells which have active biological function. Toll-like receptors isone of the key factor involved in the immune inflammation reaction, and thought to bethe principal part which mediated immune and inflammatory reaction. Tacrolimus (FK506) is a new type of immunosuppressant, which is mainly used for organ transplant,rheumatism immunological diseases and refractory nephrosis. There are reported thatFK506play suppress the immune, anti-inflammatory activity may be related to theinhibition of calcineurin (CaN), osteopontin (OPN), NF-kappaB and a variety ofinflammatory cytokine expression.
Objective
(1) The purpose of the study was to investigate inhibiting effect of the inhibitor FK506for calcineurin on renal hypertrophy and its mechanism in early diabetic rats.(2) Thestudy aimed to investigate the protective effete of FK506on the podoeytes in diabeticrat model，and evaluates its machanism.(3) The study aimed to investigate theprotective effect of FK506on renal tubule-interstitiurn in diabetic rat mode，andevaluate its machanism.(4) The study aimed to investigate the protective effect ofFK506on macrophage accumulation，proliferation and activition in the kidney of earlydiabetic rats．
Methods
Forty adult male Sprague-Dawley rats were separated into four groups at random.Control group (n=10), model group (n=10), model group treated with tacrolimus0.5mg·kg~(-1)d~(-1)(n=10), model group treated with tacrolimus~(-1).0mg·kg~(-1)d~(-1)(n=10). Diabeteswas induced with streptozotocin (65mg·kg~(-1)) in rats, and tacrolimus (0.5or~(-1).0mg·kg~(-1)d~(-1)) was orally administered once a day for4weeks. After4weeks, thefollowing determinations were done in samples: plasma glucose (BG)、liver function、kidney function and plasma lipid were determined according to standard methods.24hours urinary albumin excretion rate (AER) was determined by Enzyme Immunoassay(EIA). Relative kidney weight (RKW) and Creatinine clearance rate (Ccr) were measured. Kidney pathologic injury was observed by light microscopy and an electronmicroscope．Immunofluorescence to detect the renal tissue of Nephrin and Podocinexpression situation. The expression of Ostepontin(OPN)、NF-κB-p65、transforminggrowth factor β1(TGFβ1)、E-cadherin and alpha-smooth muscle actin (α-SMA)、Vimentin and ED-1positive cells,NF-κB-p-p65positive cells, were detected byimmunohistochemistry. TLR2and ED-1double positive cells, PCNA and ED-1doublepositive cells, TLR4and ED-1double positive cells, iNOS and ED-1double positivepositive macrophages were measured with double immunohistochemistryimmunostaining in the kidney. The expression of calcineurin (CaN),1α type Ⅳcollagen, alpha-smooth muscle actin (alpha-SMA), Nephrin, Podocin, NF-κB p65andNF-κB p-p65were detected by Western blot.
Results
1. Clinical and metabolic parameters: There was a significant increase in fasting BGand plasma lipid (P<0.01),but body weight (BW) was significantly decrease (P<0.01)in model group and FK506group compared with control group.The BG、plasma lipidand liver function of FK506group were not differnt with model group. Increased RKWwas significantly reduced by FK506treatment with1.0mg/kg (P<0.05), elevated AERwas markedly attenuated by FK506treatment with0.5and1.0mg/kg (P<0.05,0.01).Ccr was not changed by FK506treatment with0.5or1.0mg/kg.2. Renal pathologicmorphology: Comparaed with control group, indices for tubulointerstitial injury (TII)and glomerular volume (VG) were significantly increased in model group (P<0.05,0.01). Elevated glomerular volume was significantly attenuated by FK506treatmentwith0.5and1.0mg/kg (P<0.05), and increased indices for tubulointerstitial injury wereonly ameliorated by FK506treatment with1.0mg/kg (P<0.01). Under the electronmicroscope, group DM showed a significantly widened glomerular basement membrane, disordered, wide and fused podocytic-process. The above lesions in groups FK506treatment with0.5or1.0mg/kg were less compared with group DM(P＜0.05).
3. The protective effect of the FK506on the podocytes in kidney of diabetic rats:Western blot analysis noted that the expression of CaN protein was increased2.4fold inthe kidney in DM group, FK506treatment with0.5and1.0mg/kg could reduceexpression of CaN protein by38.0%and73.2%. There was a finely dotted linearepithelial staining of Nephrin and Podocin in control group glomeruli. In contrast, thestaining of glomeruli from untreated diabetic rats was attenuated, more dispersed andclustered, this diabetic-induced loss of glomerular Nephrin and Podocin expression waslargly prevented in FK506-treated diabetic rats. Western blot analysis showed that theexpression of Nephrin and Podocin protein was reduced in the kidney of diabetic rats,and FK506treatment significantly increased the expression of Nephrin and Podocinprotein (P<0.01).4. The protective effect of the FK506on therenaltubule-interstitium in kidney of diabetic rats: TGFβ1immunostaining wasfound in grestest aboundance in the glomerular and tubulointerstitial of model groupcomparaed with control group(P<0.01)，TGFβ1expression in FK506treatment with0.5and1.0mg/kg were significantly lower than that in model group(P<0.05,0.01).Compared with control group, E-cadherin in renal tubular epithelial cells wasmarkedly decreased (P<0.01), conversely, α-SMA and Vimentin significantly increasedin diabetic rats (P<0.01).FK506treatment with0.5and1.0mg/kg could reduce theincreased expression of α-SMA and Vimentin (P<0.01), at the same time, increased theexpression of E-cadherin (P<0.01). Western blot analysis noted that the expression ofα-SMA protein was increased3.5fold in the kidney in model group, FK506treatmentwith0.5and1.0mg/kg could reduced increased expression of α-SMA protein by40.7%and69.1%.The expression of1α type Ⅳcollagen in kidney were significantly increasedin model group and reduced by FK506treatment (P<0.05,0.01).
5. The effect of the FK506on macrophage accumulation, proliferation andactivition in the kidney of diabetic rats: There were marked accumulation of ED-1+cells in diabetic kidney, which were not inhibited by treatment with FK506treatment(P<0.01). ED-1and TLR2double positive cells,ED-1and TLR4double positive cellsED-1+PCNA+cells, ED-1+iNOS+cells were significantly increased in kidneys frommodel group(P<0.01), while they were significantly inhibited by FK506treatment(P<0.01). Immunohistochemistry showed that elevated NF-κB p-p65expression indiabetic rates was significantly attenuated by FK506treatment with0.5and1.0mg/kg d(P<0.01). Western blot analysis demonstrated that the expression of NF-κB p65andNF-κB p-p65in the kidney of diabetic rats were increased by5.35and7.57foldsrespectively as compared to control. FK506treatment with0.5and1.0mg/kg d couldreduce the increased expression of NF-κB p65by26.32%and47.37%, and couldreduce the increased expression of NF-κB p-p65by56.67%and70.00%.
Conclusion
FK506could ameliorate renal structure and function injury in early experimentaldiabetic rats, which mechanism may be partly correlated with suppression of NF-κBp-p65、OPN、CaN、α-SMA、Vimentin、TGFβ1and1α(IV) collagen in renal tissue.FK506can up-regulate the expression of E-cadherin, Nephrin and Podocin. IncreasedTLR2, TLR4, PCNA and iNOS expression on macrophage in the kidney of earlydiabetic rats may be correlated with inflammatory response caused by macrophageactivation. FK506may directly or indirectly downregulate TLR2, TLR4, PCNA andiNOS expression on macrophage and inhibit inflammatory response related toTLR-NF-κB signal transduction in the kidney.
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