【摘要】：研究背景與研究目的 糖尿病腎病(DN)是糖尿病(DM)最常見和最嚴(yán)重的并發(fā)癥之一,據(jù)統(tǒng)計(jì)有30%的糖尿病患者會(huì)發(fā)展成為終末期腎病,所以研究它的發(fā)病機(jī)制就顯得非常必要。長(zhǎng)期以來(lái),人們把研究的重點(diǎn)放在了腎小球損害上,但后來(lái)的研究顯示腎小管的損傷在DN的發(fā)生發(fā)展中地位同等重要,因?yàn)檠芯堪l(fā)現(xiàn)糖尿病患者尿白蛋白排泄率還在正常范圍時(shí)就已經(jīng)存在腎小管損傷了。。腎小管損害包括腎小管上皮細(xì)胞肥大、凋亡,細(xì)胞外基質(zhì)堆積等,其發(fā)病機(jī)制尚不完全明了。 Tribbles是Grosshan等在果蠅體內(nèi)新發(fā)現(xiàn)的抑制有絲分裂的核基因,也被稱為神經(jīng)細(xì)胞死亡誘導(dǎo)蛋白激酶。TRB3是Tribbles的哺乳動(dòng)物同源體TRB家族的一員,如該家族的其他成員一樣,TRB3含有一個(gè)進(jìn)化上較為保守的激酶樣結(jié)構(gòu)域,但是由于缺乏發(fā)揮催化活性的關(guān)鍵氨基酸殘基和ATP結(jié)合位點(diǎn),在現(xiàn)有的實(shí)驗(yàn)研究中都沒有發(fā)現(xiàn)激酶活性。TRB3有廣泛的生物學(xué)活性,包括可以增加胰島素抵抗及調(diào)節(jié)細(xì)胞增殖等,并且在多個(gè)細(xì)胞轉(zhuǎn)導(dǎo)通路中發(fā)揮作用,已知的有Akt通路,CDC25/String通路和MAPK通路。近期有研究報(bào)道TRB3沉默可以改善糖尿病大鼠的心肌纖維化,而Morse等發(fā)現(xiàn)TRB3在鏈脲菌素誘導(dǎo)的和自發(fā)的糖尿病小鼠腎臟中均表達(dá)增加,基于這些研究結(jié)果,我們假設(shè)TRB3同樣參與了糖尿病腎病腎臟纖維化的發(fā)生。 凋亡被認(rèn)為是糖尿病腎病發(fā)病機(jī)制的一個(gè)重要方面,因?yàn)樗鼤?huì)導(dǎo)致腎臟體積的減少和功能的下降。目前的研究已經(jīng)發(fā)現(xiàn)了糖尿病鼠模型和糖尿病病人腎臟標(biāo)本中腎小管細(xì)胞凋亡的諸多證據(jù),而TRB3與凋亡的關(guān)系一直是近年研究的熱點(diǎn),所以我們提出了TRB3可能參與了DN腎小管細(xì)胞凋亡的假設(shè)。 依據(jù)上述背景,本研究以鏈脲佐菌素(STZ)一次性腹腔內(nèi)注射建立的糖尿病大鼠為模型研究TRB3在糖尿病大鼠腎臟中的表達(dá)及其與凋亡和纖維化的關(guān)系,并借助體外培養(yǎng)的腎小管上皮細(xì)胞進(jìn)一步研究其作用機(jī)制。 研究方法 1.8周齡雄性Wistar大鼠80只,隨機(jī)分為對(duì)照組30只和糖尿病組50只,糖尿病大鼠給予一次性腹腔注射STZ60mg/kg體重,對(duì)照組大鼠給予同等劑量檸檬酸鈉緩沖液腹腔注射,于造模后8周、12周、16周及20周分別收集對(duì)照組與DM組大鼠(各7只)的血尿及腎組織進(jìn)行各指標(biāo)的檢測(cè)。實(shí)驗(yàn)室方法檢測(cè)各組大鼠的血糖、24h尿蛋白、血肌酐；PAS染色檢測(cè)大鼠腎小球纖維化情況；免疫組織化學(xué)染色、熒光定量RT-PCR及western blot檢測(cè)大鼠腎組織中TRB3、 fibronectin (FN)和Collagen Ⅰ (Col Ⅰ)的表達(dá)。造模12周后的糖尿病大鼠再隨機(jī)分為糖尿病+空白病毒組(DM+vehicle組)和糖尿病+TRB3-siRNA病毒組(DM+TRB3-siRNA組)各10只,分別注射空白病毒和攜帶TRB3-siRNA的病毒,并于4周后處死留取腎臟測(cè)TRB3、FN和Col Ⅰ的表達(dá)。體外培養(yǎng)腎小管上皮細(xì)胞,用高糖及白蛋白刺激并檢測(cè)TRB3的表達(dá)及FN和Collagen Ⅰ的分泌,用TRB3-siRNA將TRB3沉默后再次檢測(cè)FN和Col Ⅰ的分泌以揭示其與TRB3的關(guān)系。 2.8周齡雄性Wistar大鼠40只,隨機(jī)分為對(duì)照組(control組),糖尿病組(DM組),糖尿病+空白病毒組(DM+vehicle組)和糖尿病+TRB3-siRNA病毒組(DM+TRB3-siRNA組)各10只。糖尿病大鼠給予一次性腹腔注射STZ60mg/kg體重,對(duì)照組大鼠給予同等劑量檸檬酸鈉緩沖液腹腔注射,造模16周后DM+vehicle組和DM+TRB3-siRNA組分別接受尾靜脈注射空白病毒或攜帶TRB3-siRNA的病毒并于4周后處死。留取大鼠的腎組織檢測(cè)TRB3的表達(dá)和凋亡情況。體外培養(yǎng)腎小管上皮細(xì)胞,用白蛋白刺激并檢測(cè)TRB3的表達(dá)和凋亡情況,用TRB3-siRNA將TRB3沉默后再次檢測(cè)凋亡的變化以揭示TRB3與凋亡的關(guān)系,并進(jìn)一步探究Akt通路在此過(guò)程中的作用。 結(jié)果 1.TRB3介導(dǎo)糖尿病腎病腎小管細(xì)胞外基質(zhì)聚積 1.1生化指標(biāo)及組織學(xué)改變 STZ注射后,糖尿病大鼠的血糖明顯升高,24h尿蛋白排泄量也明顯增加,而血清肌酐清除率水平明顯下降,腎肥大指數(shù)水平也明顯高于正常組。PAS染色顯示DN組大鼠的腎臟表現(xiàn)為系膜區(qū)明顯的細(xì)胞外基質(zhì)沉積,腎小球硬化(GS)水平較正常組明顯升高。 1.2TRB3在糖尿病大鼠腎臟的表達(dá)增加 免疫組化結(jié)果顯示對(duì)照組大鼠的腎臟基本不表達(dá)TRB3,而DM大鼠的腎臟則有較多TRB3陽(yáng)性的細(xì)胞,并且定位于腎小管細(xì)胞,腎小球基本不表達(dá)。實(shí)時(shí)定量RT-PCR結(jié)果顯示DM組TRB3mRNA表達(dá)明顯高于對(duì)照組。Western blot結(jié)果顯示TRB3蛋白在對(duì)照組表達(dá)量非常低,而在糖尿病組則表達(dá)明顯升高。 1.3Col Ⅰ和FN的表達(dá)在糖尿病組明顯升高,而TRB3沉默后則較前明顯降低 TRB3沉默不影響24h尿蛋白排泄量。免疫組化和western blot的結(jié)果都表明Col Ⅰ和FN的表達(dá)在糖尿病組明顯升高,而TRB3沉默后則明顯降低。 1.4白蛋白可誘導(dǎo)NRK-52E細(xì)胞表達(dá)TRB3。 1.5白蛋白可誘導(dǎo)NRK-52E細(xì)胞分泌Col Ⅰ和FN,TRB3沉默后其分泌減少。 ELISA法檢測(cè)Col Ⅰ和FN發(fā)現(xiàn)白蛋白可增加二者的分泌,而用TRB3-siRNA沉默TRB3的表達(dá)以后二者的分泌明顯減少。 2.TRB3介導(dǎo)了糖尿病大鼠腎小管上皮細(xì)胞的凋亡 2.1TRB3在糖尿病大鼠腎臟的表達(dá)增加 免疫組化結(jié)果顯示對(duì)照組大鼠的腎臟基本不表達(dá)TRB3,而DM大鼠的腎臟則有較多TRB3陽(yáng)性的細(xì)胞,并且定位于腎小管細(xì)胞,腎小球基本不表達(dá)。實(shí)時(shí)定量RT-PCR結(jié)果顯示DM組TRB3mRNA表達(dá)明顯高于對(duì)照組。Western blot結(jié)果顯示TRB3蛋白在對(duì)照組表達(dá)量非常低,而在糖尿病組則表達(dá)明顯升高。 2.2糖尿病大鼠腎臟凋亡的測(cè)定及TRB3沉默對(duì)凋亡的影響 空白病毒的轉(zhuǎn)染對(duì)大鼠腎臟TRB3的表達(dá)沒有影響,而攜帶TRB3-siRNA的病毒轉(zhuǎn)染大鼠后,TRB3在mRNA和蛋白水平的表達(dá)均明顯降低。原位TUNEL測(cè)定結(jié)果顯示對(duì)照組的陽(yáng)性細(xì)胞數(shù)量很少,但是DM組的數(shù)量明顯增加,且陽(yáng)性細(xì)胞主要位于腎小管細(xì)胞,TRB3-siRNA轉(zhuǎn)染后相對(duì)于空白病毒轉(zhuǎn)染后TUNEL陽(yáng)性細(xì)胞的數(shù)量明顯降低。caspase活性檢測(cè)也證明了這一點(diǎn)。 2.3白蛋白可誘導(dǎo)NRK-52E細(xì)胞表達(dá)TRB3。 用白蛋白刺激NRK-52E細(xì)胞,TRB3的表達(dá)隨BSA濃度和刺激時(shí)間逐漸升高。 2.4白蛋白可誘導(dǎo)NRK-52E細(xì)胞凋亡,而TRB3沉默則可起一定的保護(hù)作用。 通過(guò)ssDNA ELISA法檢測(cè)凋亡率結(jié)果顯示白蛋白刺激細(xì)胞后凋亡細(xì)胞數(shù)明顯升高,而將TRB3沉默后再用白蛋白刺激凋亡細(xì)胞數(shù)較之前明顯下降,說(shuō)明TRB3介導(dǎo)了此凋亡過(guò)程,caspase活性檢測(cè)也證明了這一點(diǎn)。 2.5白蛋白通過(guò)使Akt磷酸化受阻從而引起凋亡,而TRB3沉默可部分逆轉(zhuǎn)這一過(guò)程。 Akt通路是調(diào)節(jié)細(xì)胞凋亡的主要通路之一,白蛋白刺激使得磷酸化Akt/總Akt(p-Akt/Akt)降低,而用wortmannin阻斷Akt磷酸化后,白蛋白導(dǎo)致的凋亡更加明顯,說(shuō)明Akt通路確實(shí)在此凋亡過(guò)程中發(fā)揮作用。將TRB3沉默以后,p-Akt/Akt明顯升高,伴隨著凋亡的減輕,說(shuō)明Akt通路在TRB3誘導(dǎo)的凋亡過(guò)程中發(fā)揮作用。 結(jié)論 1.TRB3在糖尿病腎病腎小管細(xì)胞中的表達(dá)上調(diào)。 2.TRB3介導(dǎo)了糖尿病腎病腎小管細(xì)胞外基質(zhì)Collagen Ⅰ和FN的分泌。 3.TPB3介導(dǎo)了糖尿病腎病腎小管細(xì)胞的凋亡過(guò)程。 4.TRB3基因沉默可改善糖尿病腎病腎小管細(xì)胞凋亡和細(xì)胞外基質(zhì)堆積。
[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.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R587.2;R692.9

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