TRB3在糖尿病肾病肾小管细胞中的表达及意义
发布时间：2018-08-11 21:44
【摘要】：研究背景与研究目的 糖尿病肾病(DN)是糖尿病(DM)最常见和最严重的并发症之一,据统计有30%的糖尿病患者会发展成为终末期肾病,所以研究它的发病机制就显得非常必要。长期以来,人们把研究的重点放在了肾小球损害上,但后来的研究显示肾小管的损伤在DN的发生发展中地位同等重要,因为研究发现糖尿病患者尿白蛋白排泄率还在正常范围时就已经存在肾小管损伤了。。肾小管损害包括肾小管上皮细胞肥大、凋亡,细胞外基质堆积等,其发病机制尚不完全明了。 Tribbles是Grosshan等在果蝇体内新发现的抑制有丝分裂的核基因,也被称为神经细胞死亡诱导蛋白激酶。TRB3是Tribbles的哺乳动物同源体TRB家族的一员,如该家族的其他成员一样,TRB3含有一个进化上较为保守的激酶样结构域,但是由于缺乏发挥催化活性的关键氨基酸残基和ATP结合位点,在现有的实验研究中都没有发现激酶活性。TRB3有广泛的生物学活性,包括可以增加胰岛素抵抗及调节细胞增殖等,并且在多个细胞转导通路中发挥作用,已知的有Akt通路,CDC25/String通路和MAPK通路。近期有研究报道TRB3沉默可以改善糖尿病大鼠的心肌纤维化,而Morse等发现TRB3在链脲菌素诱导的和自发的糖尿病小鼠肾脏中均表达增加,基于这些研究结果,我们假设TRB3同样参与了糖尿病肾病肾脏纤维化的发生。 凋亡被认为是糖尿病肾病发病机制的一个重要方面,因为它会导致肾脏体积的减少和功能的下降。目前的研究已经发现了糖尿病鼠模型和糖尿病病人肾脏标本中肾小管细胞凋亡的诸多证据,而TRB3与凋亡的关系一直是近年研究的热点,所以我们提出了TRB3可能参与了DN肾小管细胞凋亡的假设。 依据上述背景,本研究以链脲佐菌素(STZ)一次性腹腔内注射建立的糖尿病大鼠为模型研究TRB3在糖尿病大鼠肾脏中的表达及其与凋亡和纤维化的关系,并借助体外培养的肾小管上皮细胞进一步研究其作用机制。 研究方法 1.8周龄雄性Wistar大鼠80只,随机分为对照组30只和糖尿病组50只,糖尿病大鼠给予一次性腹腔注射STZ60mg/kg体重,对照组大鼠给予同等剂量柠檬酸钠缓冲液腹腔注射,于造模后8周、12周、16周及20周分别收集对照组与DM组大鼠(各7只)的血尿及肾组织进行各指标的检测。实验室方法检测各组大鼠的血糖、24h尿蛋白、血肌酐；PAS染色检测大鼠肾小球纤维化情况；免疫组织化学染色、荧光定量RT-PCR及western blot检测大鼠肾组织中TRB3、 fibronectin (FN)和Collagen Ⅰ (Col Ⅰ)的表达。造模12周后的糖尿病大鼠再随机分为糖尿病+空白病毒组(DM+vehicle组)和糖尿病+TRB3-siRNA病毒组(DM+TRB3-siRNA组)各10只,分别注射空白病毒和携带TRB3-siRNA的病毒,并于4周后处死留取肾脏测TRB3、FN和Col Ⅰ的表达。体外培养肾小管上皮细胞,用高糖及白蛋白刺激并检测TRB3的表达及FN和Collagen Ⅰ的分泌,用TRB3-siRNA将TRB3沉默后再次检测FN和Col Ⅰ的分泌以揭示其与TRB3的关系。 2.8周龄雄性Wistar大鼠40只,随机分为对照组(control组),糖尿病组(DM组),糖尿病+空白病毒组(DM+vehicle组)和糖尿病+TRB3-siRNA病毒组(DM+TRB3-siRNA组)各10只。糖尿病大鼠给予一次性腹腔注射STZ60mg/kg体重,对照组大鼠给予同等剂量柠檬酸钠缓冲液腹腔注射,造模16周后DM+vehicle组和DM+TRB3-siRNA组分别接受尾静脉注射空白病毒或携带TRB3-siRNA的病毒并于4周后处死。留取大鼠的肾组织检测TRB3的表达和凋亡情况。体外培养肾小管上皮细胞,用白蛋白刺激并检测TRB3的表达和凋亡情况,用TRB3-siRNA将TRB3沉默后再次检测凋亡的变化以揭示TRB3与凋亡的关系,并进一步探究Akt通路在此过程中的作用。 结果 1.TRB3介导糖尿病肾病肾小管细胞外基质聚积 1.1生化指标及组织学改变 STZ注射后,糖尿病大鼠的血糖明显升高,24h尿蛋白排泄量也明显增加,而血清肌酐清除率水平明显下降,肾肥大指数水平也明显高于正常组。PAS染色显示DN组大鼠的肾脏表现为系膜区明显的细胞外基质沉积,肾小球硬化(GS)水平较正常组明显升高。 1.2TRB3在糖尿病大鼠肾脏的表达增加 免疫组化结果显示对照组大鼠的肾脏基本不表达TRB3,而DM大鼠的肾脏则有较多TRB3阳性的细胞,并且定位于肾小管细胞,肾小球基本不表达。实时定量RT-PCR结果显示DM组TRB3mRNA表达明显高于对照组。Western blot结果显示TRB3蛋白在对照组表达量非常低,而在糖尿病组则表达明显升高。 1.3Col Ⅰ和FN的表达在糖尿病组明显升高,而TRB3沉默后则较前明显降低 TRB3沉默不影响24h尿蛋白排泄量。免疫组化和western blot的结果都表明Col Ⅰ和FN的表达在糖尿病组明显升高,而TRB3沉默后则明显降低。 1.4白蛋白可诱导NRK-52E细胞表达TRB3。 1.5白蛋白可诱导NRK-52E细胞分泌Col Ⅰ和FN,TRB3沉默后其分泌减少。 ELISA法检测Col Ⅰ和FN发现白蛋白可增加二者的分泌,而用TRB3-siRNA沉默TRB3的表达以后二者的分泌明显减少。 2.TRB3介导了糖尿病大鼠肾小管上皮细胞的凋亡 2.1TRB3在糖尿病大鼠肾脏的表达增加 免疫组化结果显示对照组大鼠的肾脏基本不表达TRB3,而DM大鼠的肾脏则有较多TRB3阳性的细胞,并且定位于肾小管细胞,肾小球基本不表达。实时定量RT-PCR结果显示DM组TRB3mRNA表达明显高于对照组。Western blot结果显示TRB3蛋白在对照组表达量非常低,而在糖尿病组则表达明显升高。 2.2糖尿病大鼠肾脏凋亡的测定及TRB3沉默对凋亡的影响 空白病毒的转染对大鼠肾脏TRB3的表达没有影响,而携带TRB3-siRNA的病毒转染大鼠后,TRB3在mRNA和蛋白水平的表达均明显降低。原位TUNEL测定结果显示对照组的阳性细胞数量很少,但是DM组的数量明显增加,且阳性细胞主要位于肾小管细胞,TRB3-siRNA转染后相对于空白病毒转染后TUNEL阳性细胞的数量明显降低。caspase活性检测也证明了这一点。 2.3白蛋白可诱导NRK-52E细胞表达TRB3。 用白蛋白刺激NRK-52E细胞,TRB3的表达随BSA浓度和刺激时间逐渐升高。 2.4白蛋白可诱导NRK-52E细胞凋亡,而TRB3沉默则可起一定的保护作用。 通过ssDNA ELISA法检测凋亡率结果显示白蛋白刺激细胞后凋亡细胞数明显升高,而将TRB3沉默后再用白蛋白刺激凋亡细胞数较之前明显下降,说明TRB3介导了此凋亡过程,caspase活性检测也证明了这一点。 2.5白蛋白通过使Akt磷酸化受阻从而引起凋亡,而TRB3沉默可部分逆转这一过程。 Akt通路是调节细胞凋亡的主要通路之一,白蛋白刺激使得磷酸化Akt/总Akt(p-Akt/Akt)降低,而用wortmannin阻断Akt磷酸化后,白蛋白导致的凋亡更加明显,说明Akt通路确实在此凋亡过程中发挥作用。将TRB3沉默以后,p-Akt/Akt明显升高,伴随着凋亡的减轻,说明Akt通路在TRB3诱导的凋亡过程中发挥作用。 结论 1.TRB3在糖尿病肾病肾小管细胞中的表达上调。 2.TRB3介导了糖尿病肾病肾小管细胞外基质Collagen Ⅰ和FN的分泌。 3.TPB3介导了糖尿病肾病肾小管细胞的凋亡过程。 4.TRB3基因沉默可改善糖尿病肾病肾小管细胞凋亡和细胞外基质堆积。
[Abstract]:Research background and research purpose
Diabetic nephropathy (DN) is one of the most common and serious complications of diabetes mellitus (DM). According to statistics, 30% of diabetic patients will develop end-stage renal disease, so it is necessary to study its pathogenesis. For a long time, people have focused on glomerular damage, but later studies have shown that renal tubular damage. It plays an important role in the occurrence and development of DN, because studies have found that renal tubular damage exists when the urinary albumin excretion rate of diabetic patients is within the normal range.
Tribbles is a newly discovered mitotic-suppressing nuclear gene, also known as neuronal death-inducible protein kinase, found in Drosophila by Grosshan et al. TRB3 is a member of the TRB family, a mammalian homologue of Tribbles. Like other members of the family, TRB3 contains an evolutionarily conserved kinase-like domain, but due to lack of it. The key amino acid residues and ATP binding sites that play a catalytic role have not been found in the existing experimental studies. TRB3 has a wide range of biological activities, including increasing insulin resistance and regulating cell proliferation, and plays a role in many cell transduction pathways, known as Akt pathway, CDC25/String pathway and M. Recent studies have reported that TRB3 silencing can ameliorate myocardial fibrosis in diabetic rats. Morse et al. found that TRB3 expression increased in the kidneys of streptozotocin-induced and spontaneous diabetic mice.
Apoptosis is considered to be an important aspect of the pathogenesis of diabetic nephropathy, because it leads to the decrease of renal volume and function. Therefore, we propose that TRB3 may be involved in the hypothesis of apoptosis of DN renal tubular cells.
Based on the above background, the expression of TRB3 in the kidneys of diabetic rats induced by intraperitoneal injection of streptozotocin (STZ) and the relationship between TRB3 expression and apoptosis and fibrosis were studied in this study.
research method
Eighty male Wistar rats aged 1.8 weeks were randomly divided into control group (30 rats) and diabetic group (50 rats). Diabetic rats were injected with STZ 60mg/kg body weight once intraperitoneally. The control group was injected with sodium citrate buffer intraperitoneally. Hematuria and urine of control group and DM group (7 rats in each group) were collected 8 weeks, 12 weeks, 16 weeks and 20 weeks after modeling. Kidney tissues were examined for each index. Blood glucose, 24-hour urinary protein and serum creatinine were detected by laboratory method; glomerular fibrosis was detected by PAS staining; the expressions of TRB3, fibronectin (FN) and Collagen I (Col I) were detected by immunohistochemical staining, fluorescence quantitative RT-PCR and Western blot. Diabetic rats were randomly divided into diabetes mellitus + blank virus group (DM + vehicle group) and diabetes mellitus + TRB3-siRNA group (DM + TRB3-siRNA group). Ten rats in each group were injected with blank virus and virus carrying TRB3-siRNA respectively. The kidneys were sacrificed after 4 weeks to detect the expression of TRB3, FN and Col I. Albumin stimulated and detected the expression of TRB3 and the secretion of FN and Collagen I. TRB3 was silenced by TRB3-siRNA and the secretion of FN and Col I was detected again to reveal the relationship between TRB3 and TRB3.
40 male Wistar rats aged 2.8 weeks were randomly divided into control group (control group), diabetes mellitus group (DM group), diabetes mellitus + vehicle group (DM + vehicle group) and diabetes mellitus + TRB3-siRNA virus group (DM + TRB3-siRNA group), 10 rats in each group. After 16 weeks, DM+vehicle group and DM+TRB3-siRNA group received tail vein injection of blank virus or virus carrying TRB3-siRNA respectively and were sacrificed 4 weeks later. The expression and apoptosis of TRB3 were detected in kidney tissues of rats. Renal tubular epithelial cells were cultured in vitro, and the expression and apoptosis of TRB3 were detected by albumin stimulation and T lymphocyte apoptosis. RB3-siRNA silenced TRB3 and detected apoptosis again to reveal the relationship between TRB3 and apoptosis, and further explore the role of Akt pathway in this process.
Result
1.TRB3 mediates accumulation of extracellular matrix in renal tubular cells in diabetic nephropathy
1.1 biochemical and histological changes
After STZ injection, the blood glucose, urinary protein excretion and serum creatinine clearance of diabetic rats were significantly increased, and the level of renal hypertrophy index were significantly higher than those of normal rats. PAS staining showed that the kidney of DN rats showed obvious deposition of extracellular matrix in mesangial area, and the level of glomerulosclerosis (GS) was higher than that of normal rats. Obviously increased.
Increased expression of 1.2TRB3 in kidneys of diabetic rats
Immunohistochemical staining showed that TRB3 was not expressed in the kidneys of the control group, but more TRB3-positive cells were found in the kidneys of DM rats. The expression of TRB3 mRNA in the kidneys of DM rats was significantly higher than that of the control group. Western blot showed that TRB3 protein was expressed in the control group. The amount was very low, but the expression increased significantly in diabetic group.
The expression of 1.3Col I and FN increased significantly in diabetic group, but decreased significantly after TRB3 silencing.
The results of immunohistochemistry and Western blot showed that the expression of Col I and FN increased significantly in diabetic group, but decreased significantly after TRB3 silencing.
1.4 albumin can induce NRK-52E cells to express TRB3..
1.5 albumin could induce NRK-52E cells to secrete Col I and FN, and TRB3 secreted and secreted less.
Detection of Col I and FN by ELISA showed that albumin increased the secretion of both, while TRB3-siRNA silenced the expression of TRB3 significantly decreased the secretion of both.
2.TRB3 mediates apoptosis of renal tubular epithelial cells in diabetic rats.
Increased expression of 2.1TRB3 in kidneys of diabetic rats
Immunohistochemical staining showed that TRB3 was not expressed in the kidneys of the control group, but more TRB3-positive cells were found in the kidneys of DM rats. The expression of TRB3 mRNA in the kidneys of DM rats was significantly higher than that of the control group. Western blot showed that TRB3 protein was expressed in the control group. The amount was very low, but the expression increased significantly in diabetic group.
2.2 the apoptosis of kidneys in diabetic rats and the effect of TRB3 silence on apoptosis.
In situ TUNEL assay showed that the number of positive cells in control group was very small, but the number of positive cells in DM group was significantly increased, and the positive cells were mainly located in renal tubular cells. The number of TUNEL-positive cells after TRB3-siRNA transfection was significantly lower than that after blank virus transfection. Caspase activity assay also proved this.
2.3 albumin can induce NRK-52E cells to express TRB3..
Albumin stimulated NRK-52E cells, and the expression of TRB3 increased with BSA concentration and stimulation time.
2.4 albumin can induce apoptosis of NRK-52E cells, while TRB3 silence can play a protective role.
The results of ssDNA-ELISA showed that the number of apoptotic cells increased significantly after albumin stimulation, but decreased significantly after TRB3 was silenced and then stimulated by albumin, which indicated that TRB3 mediated the process of apoptosis, and caspase activity also proved this.
2.5 Albumin induces apoptosis by blocking Akt phosphorylation, which can be partially reversed by TRB3 silencing.
Akt pathway is one of the main pathways regulating apoptosis. Albumin stimulation decreases phosphorylated Akt/Akt (p-Akt/Akt), and wortmannin blockades Akt phosphorylation, which indicates that Akt pathway does play a role in the process of apoptosis. After TRB3 silencing, p-Akt/Akt increases significantly, accompanied by apoptosis. The reduction indicates that Akt pathway plays a role in TRB3 induced apoptosis.
conclusion
1.TRB3 was upregulated in renal tubular cells of diabetic nephropathy.
2.TRB3 mediates the secretion of Collagen and FN in renal tubular extracellular matrix in diabetic nephropathy.
3.TPB3 mediates the apoptosis process of renal tubular cells in diabetic nephropathy.
4.TRB3 gene silencing can improve renal tubular cell apoptosis and extracellular matrix accumulation in diabetic nephropathy.
【学位授予单位】：山东大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R587.2;R692.9
本文编号：2178322
[Abstract]:Research background and research purpose
Diabetic nephropathy (DN) is one of the most common and serious complications of diabetes mellitus (DM). According to statistics, 30% of diabetic patients will develop end-stage renal disease, so it is necessary to study its pathogenesis. For a long time, people have focused on glomerular damage, but later studies have shown that renal tubular damage. It plays an important role in the occurrence and development of DN, because studies have found that renal tubular damage exists when the urinary albumin excretion rate of diabetic patients is within the normal range.
Tribbles is a newly discovered mitotic-suppressing nuclear gene, also known as neuronal death-inducible protein kinase, found in Drosophila by Grosshan et al. TRB3 is a member of the TRB family, a mammalian homologue of Tribbles. Like other members of the family, TRB3 contains an evolutionarily conserved kinase-like domain, but due to lack of it. The key amino acid residues and ATP binding sites that play a catalytic role have not been found in the existing experimental studies. TRB3 has a wide range of biological activities, including increasing insulin resistance and regulating cell proliferation, and plays a role in many cell transduction pathways, known as Akt pathway, CDC25/String pathway and M. Recent studies have reported that TRB3 silencing can ameliorate myocardial fibrosis in diabetic rats. Morse et al. found that TRB3 expression increased in the kidneys of streptozotocin-induced and spontaneous diabetic mice.
Apoptosis is considered to be an important aspect of the pathogenesis of diabetic nephropathy, because it leads to the decrease of renal volume and function. Therefore, we propose that TRB3 may be involved in the hypothesis of apoptosis of DN renal tubular cells.
Based on the above background, the expression of TRB3 in the kidneys of diabetic rats induced by intraperitoneal injection of streptozotocin (STZ) and the relationship between TRB3 expression and apoptosis and fibrosis were studied in this study.
research method
Eighty male Wistar rats aged 1.8 weeks were randomly divided into control group (30 rats) and diabetic group (50 rats). Diabetic rats were injected with STZ 60mg/kg body weight once intraperitoneally. The control group was injected with sodium citrate buffer intraperitoneally. Hematuria and urine of control group and DM group (7 rats in each group) were collected 8 weeks, 12 weeks, 16 weeks and 20 weeks after modeling. Kidney tissues were examined for each index. Blood glucose, 24-hour urinary protein and serum creatinine were detected by laboratory method; glomerular fibrosis was detected by PAS staining; the expressions of TRB3, fibronectin (FN) and Collagen I (Col I) were detected by immunohistochemical staining, fluorescence quantitative RT-PCR and Western blot. Diabetic rats were randomly divided into diabetes mellitus + blank virus group (DM + vehicle group) and diabetes mellitus + TRB3-siRNA group (DM + TRB3-siRNA group). Ten rats in each group were injected with blank virus and virus carrying TRB3-siRNA respectively. The kidneys were sacrificed after 4 weeks to detect the expression of TRB3, FN and Col I. Albumin stimulated and detected the expression of TRB3 and the secretion of FN and Collagen I. TRB3 was silenced by TRB3-siRNA and the secretion of FN and Col I was detected again to reveal the relationship between TRB3 and TRB3.
40 male Wistar rats aged 2.8 weeks were randomly divided into control group (control group), diabetes mellitus group (DM group), diabetes mellitus + vehicle group (DM + vehicle group) and diabetes mellitus + TRB3-siRNA virus group (DM + TRB3-siRNA group), 10 rats in each group. After 16 weeks, DM+vehicle group and DM+TRB3-siRNA group received tail vein injection of blank virus or virus carrying TRB3-siRNA respectively and were sacrificed 4 weeks later. The expression and apoptosis of TRB3 were detected in kidney tissues of rats. Renal tubular epithelial cells were cultured in vitro, and the expression and apoptosis of TRB3 were detected by albumin stimulation and T lymphocyte apoptosis. RB3-siRNA silenced TRB3 and detected apoptosis again to reveal the relationship between TRB3 and apoptosis, and further explore the role of Akt pathway in this process.
Result
1.TRB3 mediates accumulation of extracellular matrix in renal tubular cells in diabetic nephropathy
1.1 biochemical and histological changes
After STZ injection, the blood glucose, urinary protein excretion and serum creatinine clearance of diabetic rats were significantly increased, and the level of renal hypertrophy index were significantly higher than those of normal rats. PAS staining showed that the kidney of DN rats showed obvious deposition of extracellular matrix in mesangial area, and the level of glomerulosclerosis (GS) was higher than that of normal rats. Obviously increased.
Increased expression of 1.2TRB3 in kidneys of diabetic rats
Immunohistochemical staining showed that TRB3 was not expressed in the kidneys of the control group, but more TRB3-positive cells were found in the kidneys of DM rats. The expression of TRB3 mRNA in the kidneys of DM rats was significantly higher than that of the control group. Western blot showed that TRB3 protein was expressed in the control group. The amount was very low, but the expression increased significantly in diabetic group.
The expression of 1.3Col I and FN increased significantly in diabetic group, but decreased significantly after TRB3 silencing.
The results of immunohistochemistry and Western blot showed that the expression of Col I and FN increased significantly in diabetic group, but decreased significantly after TRB3 silencing.
1.4 albumin can induce NRK-52E cells to express TRB3..
1.5 albumin could induce NRK-52E cells to secrete Col I and FN, and TRB3 secreted and secreted less.
Detection of Col I and FN by ELISA showed that albumin increased the secretion of both, while TRB3-siRNA silenced the expression of TRB3 significantly decreased the secretion of both.
2.TRB3 mediates apoptosis of renal tubular epithelial cells in diabetic rats.
Increased expression of 2.1TRB3 in kidneys of diabetic rats
Immunohistochemical staining showed that TRB3 was not expressed in the kidneys of the control group, but more TRB3-positive cells were found in the kidneys of DM rats. The expression of TRB3 mRNA in the kidneys of DM rats was significantly higher than that of the control group. Western blot showed that TRB3 protein was expressed in the control group. The amount was very low, but the expression increased significantly in diabetic group.
2.2 the apoptosis of kidneys in diabetic rats and the effect of TRB3 silence on apoptosis.
In situ TUNEL assay showed that the number of positive cells in control group was very small, but the number of positive cells in DM group was significantly increased, and the positive cells were mainly located in renal tubular cells. The number of TUNEL-positive cells after TRB3-siRNA transfection was significantly lower than that after blank virus transfection. Caspase activity assay also proved this.
2.3 albumin can induce NRK-52E cells to express TRB3..
Albumin stimulated NRK-52E cells, and the expression of TRB3 increased with BSA concentration and stimulation time.
2.4 albumin can induce apoptosis of NRK-52E cells, while TRB3 silence can play a protective role.
The results of ssDNA-ELISA showed that the number of apoptotic cells increased significantly after albumin stimulation, but decreased significantly after TRB3 was silenced and then stimulated by albumin, which indicated that TRB3 mediated the process of apoptosis, and caspase activity also proved this.
2.5 Albumin induces apoptosis by blocking Akt phosphorylation, which can be partially reversed by TRB3 silencing.
Akt pathway is one of the main pathways regulating apoptosis. Albumin stimulation decreases phosphorylated Akt/Akt (p-Akt/Akt), and wortmannin blockades Akt phosphorylation, which indicates that Akt pathway does play a role in the process of apoptosis. After TRB3 silencing, p-Akt/Akt increases significantly, accompanied by apoptosis. The reduction indicates that Akt pathway plays a role in TRB3 induced apoptosis.
conclusion
1.TRB3 was upregulated in renal tubular cells of diabetic nephropathy.
2.TRB3 mediates the secretion of Collagen and FN in renal tubular extracellular matrix in diabetic nephropathy.
3.TPB3 mediates the apoptosis process of renal tubular cells in diabetic nephropathy.
4.TRB3 gene silencing can improve renal tubular cell apoptosis and extracellular matrix accumulation in diabetic nephropathy.
【学位授予单位】：山东大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R587.2;R692.9
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