NG2蛋白多糖在糖尿病肾病发病机制中的作用
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摘要
研究背景:糖尿病肾病(diabetic nephropathy, DN)的发病率在全世界范围内正在逐年升高。DN已经成为欧美诱导终末期肾衰竭需要肾替代治疗的最常见的原因。早期DN的主要特征为小球肥大和进行性细胞外基质(extracellular matrix, ECM)增加,损害逐渐加重和持续性蛋白尿导致肾小球硬化,肾功能恶化和慢性肾功能衰竭。.小球肥大和ECM积聚的分子机制涉及到多种因素和途径,是目前研究的热点。NG2是一种重要的硫酸软骨素蛋白多糖(chondroitin sulfate proteoglycan, CSPG),分子结构显示NG2具有完整的跨膜结构,可与胞外多种配体结合,并介导胞内信号转导,因此在调节细胞与细胞,细胞与ECM的相互作用中发挥了重要的功能。近年来研究者们发现NG2不仅表达在中枢神经系统(central nervous system, CNS),许多间叶细胞中也发现NG2的表达,如成软骨细胞、骨骼肌成肌细胞、表皮干细胞、血管平滑肌细胞/周细胞以及黑色素瘤细胞等。但NG2在肾脏组织中的表达、定位以及功能仍未见报道。
目的:本课题旨在观察NG2在大鼠肾脏中的表达和定位,以及NG2在糖尿病大鼠模型中的表达变化,探讨NG2与DN肾小球肥大和ECM积聚之间的关系,从而为DN的发病机制提供新的理论,并为DN的早期防治提供新的作用靶点。
方法:(1)雄性SD大鼠麻醉后,灌注固定,取肾脏皮质,免疫荧光法和免疫电镜法观察NG2在大鼠肾脏组织中的定位。取新鲜的肾脏皮质,RT-PCR法和western blot法分别检测NG2 mRNA和蛋白的表达。(2)链脲佐菌素(Streptozocin, STZ)65 mg/kg单次腹腔注射,复制糖尿病大鼠模型,分别于2、4、8周各处死6只。观察肾脏组织病理学和生化指标改变。取肾脏皮质,免疫荧光染色,荧光定量PCR法和western blot法观察NG2表达的变化(。3)体外培养大鼠肾小球系膜细胞HBZY-1,高糖(30mmol/L)刺激24 hs后观察NG2表达的变化。构建两条针对NG2的shRNA真核表达载体Pgenesil-siNG21和Pgenesil-siNG22,检测干扰效率,取效率高的质粒进行后续实验。(4)将Pgenesil-siNG2和NG2表达载体(pcDNA-NG2)转染入HBZY-1细胞,MTT法观察细胞增殖情况,流式细胞仪(flow cytometry, FCM)检测细胞周期,荧光定量PCR法观察ECM成分collagen VI和Laminin的表达变化。
结果:(1)共聚焦显微镜和免疫电镜观察均发现正常大鼠肾脏中可见NG2的表达,主要定位于肾小球系膜区,包括系膜细胞和系膜基质。RT-PCR法和western blot法分别检测NG2 mRNA和蛋白的表达,结果提示正常大鼠肾脏中NG2表达水平较低。(2)STZ腹腔注射3天后,大鼠血糖>16.7mmol/L,视为达到糖尿病诊断标准,且在处死前的8周内始终维持高血糖水平。糖尿病大鼠的血糖、肾重/体重和尿白蛋白/肌酐明显高于对照组,有统计学意义(P<0.05或P<0.01)。8周糖尿病大鼠可见明显的肾小球肥大和系膜区增生,平均肾小球体积为(1.29±0.11)x106μm3,与对照组(1.14±0.12)x106μm3相比,有统计学意义(P<0.05);电镜显示糖尿病组大鼠部分足突融合,中度系膜基质增生。免疫荧光染色显示糖尿病大鼠NG2表达也定位于系膜区,但较正常组荧光强度增加;荧光定量PCR和western blot结果显示糖尿病大鼠NG2 mRNA和蛋白表达增高。与对应时间段对照大鼠相比,2周糖尿病大鼠NG2 mRNA水平显著增高(138±76)% ,达到峰值;4周和8周糖尿病大鼠也分别增高(74±40)%和(73±37)%。(3)高糖(30mmol/L)刺激HBZY-1细胞24 hs后,NG2表达水平较正常对照组和甘露醇对照组明显升高,有统计学意义(P<0.01)。构建两条针对NG2的shRNA ( Pgenesil-siNG21和Pgenesil-siNG22 ),以及随机阴性对照Pgenesil-siNC,经酶切鉴定和DNA测序均符合设计要求。荧光定量PCR结果显示Pgenesil-siNG21和Pgenesil-siNG22对HBZY-1细胞中NG2基因的抑制率分别为54%和72%,选取Pgenesil-siNG22做后续实验。(4)将Pgenesil-siNG22、Pgenesil-siNC、NG2表达质粒(pcDNA-NG2)和空质粒pcDNA分别转染入HBZY-1细胞,MTT法检测结果显示质粒pcDNA-NG2转染组细胞吸光度值(1.309±0.018)较对照组pcDNA转染组(1.016±0.031)明显增加,有显著统计学意义(P<0.01);而质粒Pgenesil-siNG22转染组细胞吸光度值(0.835±0.038)较对照组Pgenesil-siNC转染组(1.021±0.049)明显下降,有统计学意义(P<0.05),提示NG2基因对HBZY-1细胞有促进增殖的作用。FCM结果显示质粒pcDNA-NG2转染组和Pgenesil-siNG22转染组细胞周期中位于S期的比例分别为17.66%和2.88%,较对照组(10.46%和10.47%)有统计学意义(P<0.05)。荧光定量PCR法结果显示质粒pcDNA-NG2转染组细胞α2 (VI) collagen和Lamininβ1 mRNA表达较对照组明显升高,有统计学意义(P<0.05);而质粒Pgenesil-siNG22转染组细胞α2 (VI) collagen和Lamininβ1 mRNA表达较对照组显著减少,有统计学意义(P<0.05或P<0.01)。
结论:(1)NG2在大鼠肾脏中有表达,主要定位于肾小球系膜区,包括系膜细胞和系膜基质。(2)糖尿病大鼠肾脏NG2表达明显增加,并有时序性改变,2周时达到高峰,后维持较高水平至观察的第8周。(3)体外高糖刺激肾小球系膜细胞可见NG2表达的升高。从沉默和过表达NG2两方面的实验观察发现,NG2基因有促进系膜细胞增殖和ECM成分collagen VI和Laminin增生的作用。(4)因此,NG2可能是参与DN发生进展的重要因子。本课题为DN发病机制的研究提供了新的理论,为DN的早期防治提供了新的作用靶点。
Background: Diabetic nephropathy is increasing dramatically worldwide and is now the most common cause of end-stage renal failure requiring renal replacement therapy in Europe and America. Glomerular hypertrophy and progressive expansion of extracellular matrix (ECM) have been supposed to be the early features of diabetic nephropathy. It is believed that with the progression of these lesions and persistent proteinuria, glomerular sclerosis occurs, which lead to deterioration of renal function and chronic renal failure. Molecular mechanisms underlying the pathogenesis of glomerular hypertrophy and ECM accumulation have, however, remained incompletely understood. NG2 is a large, integral membrane-spanning chondroitin sulfate proteoglycan (CSPG). It is capable of binding to multiple extracellular ligands and participating in cytoplasmic signal transduction. NG2 plays an important role in mediating the cellular interactions or interactions between cells and ECM. NG2 is expressed not only in central nervous system, but also in a variety of mesenchymal cell types such as chondroblasts, skeletal myoblasts, epidermal stem cells, vascular smooth cells/pericytes and melanoma cells. But the expression and role of NG2 in kidneys has not been clarified.
Objective: To investigate the expression of NG2 proteoglycan in the kidneys of normal rats and strepozotocin (STZ)-induced diabetic rats, and observe the role of NG2 in the pathogenesis of diabetic nephropathy.
Methods: (1) Sprague-Dawley rats were anaesthetized and perfusion-fixed. Immunohistochemistry and immunoelectron microscopy was performed to examine the location of NG2 in rat kidneys. The expression of mRNA and protein of NG2 was measured by RT-PCR and western blot respectively. (2) To induce diabetes, rats were given a single intraperitoneal injection of 65 mg/kg Streptozocin (STZ). 2, 4 and 8 weeks after injection, 6 animals of each group were sacrificed and kidneys were removed for the further investigations. Biochemical parameters and pathological changes were examined. The expression of NG2 was detected by immunohistochemistry, real-time PCR and western blot. (3) Rat glomerular mesangial cell line HBZY-1 was cultured in vitro. HBZY-1 cells were treated with high glucose (30mmol/L) for 24 hs and the changes of NG2 expression were observed. Two small hairpin RNA (shRNA) constructs targeting NG2 were created, and the interference efficiency was measured. The better construct was selected to perform the next experiments. (4) HBZY-1 cells were transfected with Pgenesil-siNG2 and NG2 expression vectors (pcDNA-NG2) by LipofectamineTM 2000. The effect of NG2 on the proliferation of HBZY-1 cells was examined by MTT method and flow cytometry (FCM), and the effect of NG2 on the synthesis of collagen VI and Laminin was measured by real-time PCR.
Results: (1) The location of NG2 proteoglycan in kidneys was investigated by confocal microscopy and immunoelectron microscopy. NG2 was mainly expressed in the mesangial matrix and mesangial cells of glomeruli. The expression of mRNA and protein of NG2 in rat kidneys was detected by RT-PCR and western blot. (2) Rats with blood glucose concentration>16.7mmol/L were accepted as diabetic models 3 days after STZ injection. Hyperglycemia persisted in diabetic animals during the 8 weeks study period before they were sacrificed. The blood glucose level, kidney-to-body weigh ratio and urinary albumin/creatinine of diabetic rats were significantly higher than those of control rats (P<0.05 or P<0.01). Glomerular hypertrophy and mesangial expansion were evident in 8 week diabetic rats. There was a significant increase of mean VG from (1.14±0.12) to (1.29±0.11) x106μm3 (P<0.05). The electron micrographs showed segmental fusion of podocyte foot processes and moderate mesangial matrix expansion. The expression of NG2 was also observed predominantly in glomerular mesangium in diabetic rats. Compared with control rats, the expression of NG2 in renal cortex was significantly higher than that in diabetic rats. The NG2 mRNA levels peaked within 2 weeks (increase by 138±76%, P<0.01) and still remained significantly enhanced 4 weeks (by 74±40%, P<0.05) and 8 weeks (by 73±37%, P<0.01) in diabetic rats compared with time-match control rats. (3) The expression of NG2 in HBZY-1 cells significantly increased (P<0.01) after treated with high glucose (30mmol/L) for 24 hs. Two shRNA vectors targeting NG2 (Pgenesil-siNG21 and Pgenesil-siNG22) were constructed successfully, and their interference efficiency was 54% and 72% respectively. Pgenesil-siNG22 was selected to perform the next experiments. (4) HBZY-1 cells were transfected with Pgenesil-siNG22, Pgenesil-siNC, pcDNA-NG2 and empty vector pcDNA respectively. According to MTT assay, overexpression of NG2 significantly stimulated, while NG2 silencing inhibited the proliferation of mesangial cells. The data of cell-cycle analysis by FCM showed that NG2 increased the cell numbers in the S phase and decreased the cell number in the G0/G1 phase, while silencing NG2 induced decrease of the cell numbers in the S phase and increase of the cell numbers in the G0/G1 phase. The expression of collagen VI and Laminin was significantly increased by overexpressing of NG2 and was decreased by treating with NG2 siRNA.
Conclusions: In the kidneys of normal and STZ-induced diabetic rats, the expression of NG2 was observed predominantly in glomerular mesangium. Both mRNA and protein levels were significantly higher in diabetic rats than those in control rats. In cultured rat mesangial cell line HBZY-1, overexpression of NG2 promoted cell proliferation and formation of ECM such as type VI collagen and Laminin. Furthermore, gene silencing targeting NG2 resuLted in decreased cell proliferation and formation of ECM. The observations suggest that NG2 is up-regulated in diabetic nephropathy and actively participates in the development and progression of glomerulosclerosis by stimulating the proliferation of mesangial cells and the deposition of ECM. NG2 is a potential target for prevention and therapy of DN.
目的:本课题旨在观察NG2在大鼠肾脏中的表达和定位,以及NG2在糖尿病大鼠模型中的表达变化,探讨NG2与DN肾小球肥大和ECM积聚之间的关系,从而为DN的发病机制提供新的理论,并为DN的早期防治提供新的作用靶点。
方法:(1)雄性SD大鼠麻醉后,灌注固定,取肾脏皮质,免疫荧光法和免疫电镜法观察NG2在大鼠肾脏组织中的定位。取新鲜的肾脏皮质,RT-PCR法和western blot法分别检测NG2 mRNA和蛋白的表达。(2)链脲佐菌素(Streptozocin, STZ)65 mg/kg单次腹腔注射,复制糖尿病大鼠模型,分别于2、4、8周各处死6只。观察肾脏组织病理学和生化指标改变。取肾脏皮质,免疫荧光染色,荧光定量PCR法和western blot法观察NG2表达的变化(。3)体外培养大鼠肾小球系膜细胞HBZY-1,高糖(30mmol/L)刺激24 hs后观察NG2表达的变化。构建两条针对NG2的shRNA真核表达载体Pgenesil-siNG21和Pgenesil-siNG22,检测干扰效率,取效率高的质粒进行后续实验。(4)将Pgenesil-siNG2和NG2表达载体(pcDNA-NG2)转染入HBZY-1细胞,MTT法观察细胞增殖情况,流式细胞仪(flow cytometry, FCM)检测细胞周期,荧光定量PCR法观察ECM成分collagen VI和Laminin的表达变化。
结果:(1)共聚焦显微镜和免疫电镜观察均发现正常大鼠肾脏中可见NG2的表达,主要定位于肾小球系膜区,包括系膜细胞和系膜基质。RT-PCR法和western blot法分别检测NG2 mRNA和蛋白的表达,结果提示正常大鼠肾脏中NG2表达水平较低。(2)STZ腹腔注射3天后,大鼠血糖>16.7mmol/L,视为达到糖尿病诊断标准,且在处死前的8周内始终维持高血糖水平。糖尿病大鼠的血糖、肾重/体重和尿白蛋白/肌酐明显高于对照组,有统计学意义(P<0.05或P<0.01)。8周糖尿病大鼠可见明显的肾小球肥大和系膜区增生,平均肾小球体积为(1.29±0.11)x106μm3,与对照组(1.14±0.12)x106μm3相比,有统计学意义(P<0.05);电镜显示糖尿病组大鼠部分足突融合,中度系膜基质增生。免疫荧光染色显示糖尿病大鼠NG2表达也定位于系膜区,但较正常组荧光强度增加;荧光定量PCR和western blot结果显示糖尿病大鼠NG2 mRNA和蛋白表达增高。与对应时间段对照大鼠相比,2周糖尿病大鼠NG2 mRNA水平显著增高(138±76)% ,达到峰值;4周和8周糖尿病大鼠也分别增高(74±40)%和(73±37)%。(3)高糖(30mmol/L)刺激HBZY-1细胞24 hs后,NG2表达水平较正常对照组和甘露醇对照组明显升高,有统计学意义(P<0.01)。构建两条针对NG2的shRNA ( Pgenesil-siNG21和Pgenesil-siNG22 ),以及随机阴性对照Pgenesil-siNC,经酶切鉴定和DNA测序均符合设计要求。荧光定量PCR结果显示Pgenesil-siNG21和Pgenesil-siNG22对HBZY-1细胞中NG2基因的抑制率分别为54%和72%,选取Pgenesil-siNG22做后续实验。(4)将Pgenesil-siNG22、Pgenesil-siNC、NG2表达质粒(pcDNA-NG2)和空质粒pcDNA分别转染入HBZY-1细胞,MTT法检测结果显示质粒pcDNA-NG2转染组细胞吸光度值(1.309±0.018)较对照组pcDNA转染组(1.016±0.031)明显增加,有显著统计学意义(P<0.01);而质粒Pgenesil-siNG22转染组细胞吸光度值(0.835±0.038)较对照组Pgenesil-siNC转染组(1.021±0.049)明显下降,有统计学意义(P<0.05),提示NG2基因对HBZY-1细胞有促进增殖的作用。FCM结果显示质粒pcDNA-NG2转染组和Pgenesil-siNG22转染组细胞周期中位于S期的比例分别为17.66%和2.88%,较对照组(10.46%和10.47%)有统计学意义(P<0.05)。荧光定量PCR法结果显示质粒pcDNA-NG2转染组细胞α2 (VI) collagen和Lamininβ1 mRNA表达较对照组明显升高,有统计学意义(P<0.05);而质粒Pgenesil-siNG22转染组细胞α2 (VI) collagen和Lamininβ1 mRNA表达较对照组显著减少,有统计学意义(P<0.05或P<0.01)。
结论:(1)NG2在大鼠肾脏中有表达,主要定位于肾小球系膜区,包括系膜细胞和系膜基质。(2)糖尿病大鼠肾脏NG2表达明显增加,并有时序性改变,2周时达到高峰,后维持较高水平至观察的第8周。(3)体外高糖刺激肾小球系膜细胞可见NG2表达的升高。从沉默和过表达NG2两方面的实验观察发现,NG2基因有促进系膜细胞增殖和ECM成分collagen VI和Laminin增生的作用。(4)因此,NG2可能是参与DN发生进展的重要因子。本课题为DN发病机制的研究提供了新的理论,为DN的早期防治提供了新的作用靶点。
Background: Diabetic nephropathy is increasing dramatically worldwide and is now the most common cause of end-stage renal failure requiring renal replacement therapy in Europe and America. Glomerular hypertrophy and progressive expansion of extracellular matrix (ECM) have been supposed to be the early features of diabetic nephropathy. It is believed that with the progression of these lesions and persistent proteinuria, glomerular sclerosis occurs, which lead to deterioration of renal function and chronic renal failure. Molecular mechanisms underlying the pathogenesis of glomerular hypertrophy and ECM accumulation have, however, remained incompletely understood. NG2 is a large, integral membrane-spanning chondroitin sulfate proteoglycan (CSPG). It is capable of binding to multiple extracellular ligands and participating in cytoplasmic signal transduction. NG2 plays an important role in mediating the cellular interactions or interactions between cells and ECM. NG2 is expressed not only in central nervous system, but also in a variety of mesenchymal cell types such as chondroblasts, skeletal myoblasts, epidermal stem cells, vascular smooth cells/pericytes and melanoma cells. But the expression and role of NG2 in kidneys has not been clarified.
Objective: To investigate the expression of NG2 proteoglycan in the kidneys of normal rats and strepozotocin (STZ)-induced diabetic rats, and observe the role of NG2 in the pathogenesis of diabetic nephropathy.
Methods: (1) Sprague-Dawley rats were anaesthetized and perfusion-fixed. Immunohistochemistry and immunoelectron microscopy was performed to examine the location of NG2 in rat kidneys. The expression of mRNA and protein of NG2 was measured by RT-PCR and western blot respectively. (2) To induce diabetes, rats were given a single intraperitoneal injection of 65 mg/kg Streptozocin (STZ). 2, 4 and 8 weeks after injection, 6 animals of each group were sacrificed and kidneys were removed for the further investigations. Biochemical parameters and pathological changes were examined. The expression of NG2 was detected by immunohistochemistry, real-time PCR and western blot. (3) Rat glomerular mesangial cell line HBZY-1 was cultured in vitro. HBZY-1 cells were treated with high glucose (30mmol/L) for 24 hs and the changes of NG2 expression were observed. Two small hairpin RNA (shRNA) constructs targeting NG2 were created, and the interference efficiency was measured. The better construct was selected to perform the next experiments. (4) HBZY-1 cells were transfected with Pgenesil-siNG2 and NG2 expression vectors (pcDNA-NG2) by LipofectamineTM 2000. The effect of NG2 on the proliferation of HBZY-1 cells was examined by MTT method and flow cytometry (FCM), and the effect of NG2 on the synthesis of collagen VI and Laminin was measured by real-time PCR.
Results: (1) The location of NG2 proteoglycan in kidneys was investigated by confocal microscopy and immunoelectron microscopy. NG2 was mainly expressed in the mesangial matrix and mesangial cells of glomeruli. The expression of mRNA and protein of NG2 in rat kidneys was detected by RT-PCR and western blot. (2) Rats with blood glucose concentration>16.7mmol/L were accepted as diabetic models 3 days after STZ injection. Hyperglycemia persisted in diabetic animals during the 8 weeks study period before they were sacrificed. The blood glucose level, kidney-to-body weigh ratio and urinary albumin/creatinine of diabetic rats were significantly higher than those of control rats (P<0.05 or P<0.01). Glomerular hypertrophy and mesangial expansion were evident in 8 week diabetic rats. There was a significant increase of mean VG from (1.14±0.12) to (1.29±0.11) x106μm3 (P<0.05). The electron micrographs showed segmental fusion of podocyte foot processes and moderate mesangial matrix expansion. The expression of NG2 was also observed predominantly in glomerular mesangium in diabetic rats. Compared with control rats, the expression of NG2 in renal cortex was significantly higher than that in diabetic rats. The NG2 mRNA levels peaked within 2 weeks (increase by 138±76%, P<0.01) and still remained significantly enhanced 4 weeks (by 74±40%, P<0.05) and 8 weeks (by 73±37%, P<0.01) in diabetic rats compared with time-match control rats. (3) The expression of NG2 in HBZY-1 cells significantly increased (P<0.01) after treated with high glucose (30mmol/L) for 24 hs. Two shRNA vectors targeting NG2 (Pgenesil-siNG21 and Pgenesil-siNG22) were constructed successfully, and their interference efficiency was 54% and 72% respectively. Pgenesil-siNG22 was selected to perform the next experiments. (4) HBZY-1 cells were transfected with Pgenesil-siNG22, Pgenesil-siNC, pcDNA-NG2 and empty vector pcDNA respectively. According to MTT assay, overexpression of NG2 significantly stimulated, while NG2 silencing inhibited the proliferation of mesangial cells. The data of cell-cycle analysis by FCM showed that NG2 increased the cell numbers in the S phase and decreased the cell number in the G0/G1 phase, while silencing NG2 induced decrease of the cell numbers in the S phase and increase of the cell numbers in the G0/G1 phase. The expression of collagen VI and Laminin was significantly increased by overexpressing of NG2 and was decreased by treating with NG2 siRNA.
Conclusions: In the kidneys of normal and STZ-induced diabetic rats, the expression of NG2 was observed predominantly in glomerular mesangium. Both mRNA and protein levels were significantly higher in diabetic rats than those in control rats. In cultured rat mesangial cell line HBZY-1, overexpression of NG2 promoted cell proliferation and formation of ECM such as type VI collagen and Laminin. Furthermore, gene silencing targeting NG2 resuLted in decreased cell proliferation and formation of ECM. The observations suggest that NG2 is up-regulated in diabetic nephropathy and actively participates in the development and progression of glomerulosclerosis by stimulating the proliferation of mesangial cells and the deposition of ECM. NG2 is a potential target for prevention and therapy of DN.
引文
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