【摘要】：文獻(xiàn)研究:糖尿病腎病(diabetic nephropathy,DN)是糖尿病較為常見的微血管并發(fā)癥之一,也是導(dǎo)致患者出現(xiàn)終末期腎臟疾病以及進(jìn)行腎替代治療的首要原因,嚴(yán)重地威脅著人們的健康。據(jù)研究報(bào)道,大約15%～40%的糖尿病患者會(huì)發(fā)展為糖尿病腎病。在我國,DN導(dǎo)致的終末期腎病的比例正在逐年上升,預(yù)計(jì)在不久的將來DN將成為終末期腎病最主要的原因。然而,DN的發(fā)病機(jī)制極其復(fù)雜,其具體機(jī)制至今尚未完全闡明清楚,可能是多種因素綜合作用的結(jié)果,由于眾多生物活性物質(zhì)參與了 DN的發(fā)病過程,使其病理生理機(jī)制具有多途徑、多環(huán)節(jié)相互作用的特點(diǎn),故對其進(jìn)行有效的防治一直是臨床的難題。因此,探究DN的發(fā)病機(jī)制,尋求延緩DN進(jìn)展的治療方法具有重要的社會(huì)意義及經(jīng)濟(jì)價(jià)值。在整體觀念、辨證論治等思想指導(dǎo)下,中醫(yī)藥在防治糖尿病及其并發(fā)癥方面有獨(dú)特的優(yōu)勢。中藥復(fù)方在干預(yù)防治疾病方面具有多途徑、多靶點(diǎn)的特點(diǎn),因此,運(yùn)用中藥復(fù)方防治DN具有較大的潛力。中醫(yī)學(xué)對糖尿病及其并發(fā)癥的認(rèn)識(shí)源遠(yuǎn)流長,早在《黃帝內(nèi)經(jīng)》就有消渴病的相關(guān)記載,歷代醫(yī)家、后世學(xué)者對消渴病及其并發(fā)癥的病因病機(jī)認(rèn)識(shí)不斷發(fā)展,診治水平不斷提高�？偨Y(jié)古今中醫(yī)藥辨治DN的文獻(xiàn),DN早期以氣陰兩虛、瘀熱互結(jié)為基本病機(jī),治療宜益氣養(yǎng)陰、瀉熱逐瘀。降糖三黃片乃我校熊曼琪教授及其研究團(tuán)隊(duì)在經(jīng)方桃核承氣湯的基礎(chǔ)上加減化裁而成,在臨床上治療糖尿病腎病已二十余年,取得了良好的臨床療效。為進(jìn)一步證實(shí)該方的治療作用,更深入探討其可能的作用機(jī)制,我們進(jìn)行了本項(xiàng)研究,即借助糖尿病腎病的動(dòng)物模型,觀察其對早期糖尿病腎病大鼠干預(yù)作用及對microRNA-21信號(hào)通路的影響。實(shí)驗(yàn)研究:目的:利用糖尿病腎病模型大鼠,觀察降糖三黃片對模型大鼠糖脂代謝水平、腎功能、腎組織病理改變以及microRNA-21信號(hào)通路的影響,以探明降糖三黃片防治DN的作用機(jī)制,為降糖三黃片的臨床應(yīng)用提供現(xiàn)代生物學(xué)方面的實(shí)驗(yàn)依據(jù)與支持。方法:選取80只雄性SD大鼠,適應(yīng)性喂養(yǎng)1周后,依據(jù)體重隨機(jī)將其分成正常組10只和造模組70只。造模前禁食不禁水12 h,將配制好的STZ溶液按45 mg· kg-1的劑量一次性腹腔注射,正常組腹腔注射等量的檸檬酸緩沖液。全部大鼠在同一動(dòng)物房內(nèi)用代謝籠分籠飼養(yǎng),標(biāo)準(zhǔn)飲食,不使用胰島素及其他降糖藥物。連續(xù)喂養(yǎng)3周,然后測血糖、尿量,若血糖16.7 mmol ·L-1、尿量原尿量150%、24小時(shí)尿蛋白定量30mg以上,則可確定大鼠DN模型造模成功。造模期間大鼠死亡3只,血糖自行恢復(fù)3只,血糖達(dá)標(biāo)但尿蛋白低于標(biāo)準(zhǔn)的大鼠8只,因此成模的DN大鼠共56只。將成模大鼠隨機(jī)分為模型組12只,降糖三黃片低劑量組11只,降糖三黃片中劑量組11只,降糖三黃片高劑量組11只,厄貝沙坦組11只。造模前后均以清潔級普通飼料喂養(yǎng)。降糖三黃片低劑量組按0.675g·kg-1給藥,降糖三黃片中劑量組1.350 g·kg-1給藥,降糖三黃片高劑量組2.700g·kg-1給藥,厄貝沙坦組0.0135g·kg-1給藥,灌胃前藥物均用純凈水配成2ml混懸液,每日1次灌胃,連續(xù)8w。正常組及模型組予以灌服等量蒸餾水。實(shí)驗(yàn)期間大鼠自由進(jìn)食、飲水。實(shí)驗(yàn)期間觀察大鼠的一般情況,每隔4周測大鼠體重及尾尖FBG,末次給藥后計(jì)24 h尿量及飲水量。實(shí)驗(yàn)結(jié)束時(shí)測大鼠腎功能(BUN、Scr),血脂(TC、TG、LDL-C、HDL-C),糖化血紅蛋白(HbA1c),24h尿蛋白(Upro);取大鼠腎臟,計(jì)算腎重、相對腎重;光鏡及電鏡觀察大鼠腎臟組織病理形態(tài);免疫組化法觀察大鼠腎臟TGF-β1、Smad3、Smad7的染色情況;Western blotting法檢測各組大鼠腎臟TGF-β1、Smad3、Smad7蛋白的表達(dá);RTQ-PCR法檢測各組大鼠腎臟TGF-β1、Smad3、Smad7、microRNA-21 mRNA 的表達(dá)。結(jié)果:1.體重、飲水量及尿量方面:體重方面,藥物干預(yù)4周及8周后,較模型組,藥物干預(yù)組體重均有明顯增加(P0.01),其中以降糖三黃片高劑量組效果最好,降糖三黃片中劑量組次之,而降糖三黃片低劑量組與厄貝沙坦組無差異(P0.05)。飲水方面,較模型組,降糖三黃片中劑量組、降糖三黃片高劑量組、厄貝沙坦組有所減少(P0.01),而降糖三黃片低劑量組則無明顯差異(P0.05);與厄貝沙坦組比較,降糖三黃片低劑量組、降糖三黃片中劑量組無明顯差異(P0.05),而降糖三黃片高劑量組明顯少于厄貝沙坦組(P0.01)。尿量方面,降糖三黃片中劑量組、降糖三黃片高劑量組、厄貝沙坦組有所減少(P0.01),而降糖三黃片低劑量組則無明顯差異(P0.05);與厄貝沙坦組比較,降糖三黃片高劑量組尿量減少(P0.05),而降糖三黃片中劑量組無差異(P0.05),降糖三黃片低劑量組則高于厄貝沙坦組(P0.05)。2.糖脂代謝方面:空腹血糖方面,治療4周后及8周后,降糖三黃片低劑量組、降糖三黃片中劑量組、降糖三黃片高劑量組均明顯低于模型組及厄貝沙坦組(P0.01),模型組與厄貝沙坦組則無差異(P0.05)。糖化血紅蛋白方面,治療8周后,降糖三黃片低劑量組、降糖三黃片中劑量組、降糖三黃片高劑量組均明顯低于模型組及厄貝沙坦組(P0.01),模型組與厄貝沙坦組則無差異(P0.05)。TC、TG、LDL-C方面,治療8周后,降糖三黃片低劑量組、降糖三黃片中劑量組、降糖三黃片高劑量組均明顯低于模型組及厄貝沙坦組(P0.01),模型組與厄貝沙坦組則無差異(P0.05)。HDL-C方面,與模型組比較,降糖三黃片中劑量組、降糖三黃片高劑量組明顯升高(P0.01),而降糖三黃片低劑量組、厄貝沙坦組與模型組無明顯差異(P0.05)。3.腎重、相對腎重、腎功能及尿蛋白方面:腎重方面,降糖三黃片中劑量組、降糖三黃片高劑量組、厄貝沙坦組明顯低于模型組(P0.01),而降糖三黃片低劑量組與模型組無明顯差異(P0.05),降糖三黃片中劑量組、降糖三黃片高劑量組與厄貝沙坦組無明顯差異(P0.05),而而降糖三黃片低劑量組則明顯高于厄貝沙坦組(P0.01)。相對腎重方面,藥物干預(yù)組明顯低于模型組(P0.01),降糖三黃片中劑量組、降糖三黃片高劑量組與厄貝沙坦組無明顯差異(P0.05),而降糖三黃片低劑量組則明顯高于厄貝沙坦組(P0.01)。腎功能方面(BUN、Scr),藥物干預(yù)組明顯低于模型組(P0.01),降糖三黃片高劑量組相較厄貝沙坦組無明顯差異(P0.05),而降糖三黃片低劑量、降糖三黃片中劑量組則明顯高于厄貝沙坦組(P0.01)。24 h尿蛋白方面,治療前模型組與藥物干預(yù)組,組間無明顯差異(P0.05),治療8周后,與模型組比較,降糖三黃片低劑量組降低(P0.05),降糖三黃片中劑量組、降糖三黃片高劑量組、厄貝沙坦組降低更為明顯(P0.01);與厄貝沙坦組比較,降糖三黃片高劑量組無明顯差異(P0.05),降糖三黃片低劑量組、降糖三黃片中劑量組則明顯高于厄貝沙坦組(P0.01)。4.光鏡及電鏡下觀察腎臟病理形態(tài):正常組大鼠腎臟未見病理改變,模型組大鼠腎臟病變嚴(yán)重,可見腎小球體積增大明顯,腎小球腫脹、充血,腎小囊變窄,腎小球系膜細(xì)胞增生,部分腎小管細(xì)胞肥大,部分可見空泡變性,毛細(xì)血管管腔狹窄,足突扁平,結(jié)構(gòu)不清,線粒體空泡樣變,系膜基質(zhì)增多,腎小管上皮細(xì)胞脫落、減少或萎縮。降糖三黃片低劑量組、降糖三黃片中劑量組、降糖三黃片高劑量組、厄貝沙坦組均能改善DN腎臟組織病變,其中以降糖三黃片高劑量組效果最好。5.腎臟TGF-β 1、Smad3、Smad7蛋白表達(dá):免疫組化染色結(jié)果顯示,較正常組,模型組TGF-β1、Smad3蛋白表達(dá)明顯增多(P0.01),呈棕黃色顆粒,著色極深,藥物干預(yù)組介于正常組與模型組之間,明顯低于模型組(P0.01);與厄貝沙坦組比較,降糖三黃片高劑量組無明顯差異(P0.05),降糖三黃片低劑量組、降糖三黃片中劑量組高于厄貝沙坦組(P0.05)。較模型組,藥物干預(yù)組Smad7表達(dá)明顯增多(P0.01);厄貝沙坦組Smad7表達(dá)明顯高于降糖三黃片低劑量組、降糖三黃片中劑量組、降糖三黃片高劑量組(P0.01)。Western blotting法測量TGF-β1、Smad3、Smad7蛋白表達(dá)顯示:較正常組,模型組TGF-β1、Smad3蛋白表達(dá)明顯增加(P0.01),降糖三黃片低劑量組低于模型組(P0.05),降糖三黃片中劑量組、降糖三黃片高劑量組、厄貝沙坦組明顯低于模型組(P0.01);降糖三黃片高劑量組TGF-β1、Smad3蛋白表達(dá)與厄貝沙坦組相比無明顯差異(P0.05),且厄貝沙坦組優(yōu)于降糖三黃片低劑量組及降糖三黃片中劑量組(P0.01或P0.05)。較正常組,模型組Smad7蛋白表達(dá)明顯減少(P0.01),藥物干預(yù)組明顯高于模型組(P0.01),厄貝沙坦組Smad7蛋白表達(dá)明顯高于降糖三黃片低劑量組、降糖三黃片中劑量組(P0.01),而與降糖三黃片高劑量組無明顯差異(P0.05)。6.RTQ-PCR 法檢測大鼠腎臟 TGF-β1、Smad3、Smad7、microRNA-21 mRNA 表達(dá)顯示:以正常組基因表達(dá)為參照,模型組TGF-β1、Smad3、microRNA-21mRNA基因表達(dá)顯著增多(P0.01),藥物干預(yù)組較模型組明顯降低(P0.01),降糖三黃片高劑量組與厄貝沙坦組無明顯差異(P0.05),而降糖三黃片低劑量組、降糖三黃片中劑量組明顯高于厄貝沙坦組(P0.01)。以正常組基因表達(dá)為參照,模型組Smad7 mmRNA基因表達(dá)顯著減少(P0.01),藥物干預(yù)組較模型組明顯升高(P0.01),降糖三黃片高劑量組與厄貝沙坦組無明顯差異(P0.05),而降糖三黃片低劑量組、降糖三黃片中劑量組明顯低于厄貝沙坦組(P0.01)。結(jié)論:1.在總結(jié)前人各醫(yī)家關(guān)于消渴病因病機(jī)及證治的基礎(chǔ)上,總結(jié)糖尿病腎病病機(jī)屬虛實(shí)夾雜,正虛為本,邪實(shí)為標(biāo),治以扶正祛邪為法,集益氣養(yǎng)陰、瀉熱逐瘀、通陽活血、通腑泄?jié)嵊谝惑w,可有效防治本病。2.降糖三黃片可以改善DN大鼠的一般狀態(tài),具降低血糖、調(diào)節(jié)血脂的作用。3.降糖三黃片可以降低DN大鼠的尿蛋白,降低血清BUN及Scr,具有一定保護(hù)DN大鼠腎功能的作用。4.降糖三黃片可以改善DN大鼠腎臟組織病理損害,具一定的延緩腎臟病理損傷的作用。5.降糖三黃片可以下調(diào)DN大鼠腎臟中TGF-β 1、Smad3蛋白的表達(dá),上調(diào)Smad7蛋白的表達(dá);降糖三黃片可以下調(diào)DN大鼠腎臟中TGF-β1、Smad3、microRNA-21mRNA的表達(dá),上調(diào)Smad7 mRNA的表達(dá),從而調(diào)控了 DN的microRNA-21及其TGF-β 1/Smad的信號(hào)通路轉(zhuǎn)導(dǎo),延緩了 DN的病程進(jìn)展。
[Abstract]:Literature review: Diabetic nephropathy (DN) is one of the most common microvascular complications in diabetes mellitus, and is also the leading cause of end-stage renal disease and renal replacement therapy, which seriously threatens people's health. According to research reports, about 15%-40% of diabetic patients will develop diabetes mellitus. Nephropathy. In China, the proportion of end-stage kidney disease caused by DN is increasing year by year. It is expected that DN will be the main cause of end-stage kidney disease in the near future. However, the pathogenesis of DN is extremely complex, and its specific mechanism has not been fully clarified yet. It may be the result of a combination of many factors, due to many bioactive substances. Therefore, it is of great social and economic significance to explore the pathogenesis of DN and seek treatment methods to delay the progress of DN. Under the guidance of traditional Chinese medicine, it has unique advantages in the prevention and treatment of diabetes mellitus and its complications. Traditional Chinese medicine compound prescriptions have many ways and targets in the prevention and treatment of diseases. Therefore, the use of traditional Chinese medicine compound prescriptions for the prevention and treatment of DN has great potential. Summarize the ancient and modern Chinese medicine treatment of DN literature, DN early to Qi and Yin deficiency, blood stasis and heat interlinked as the basic pathogenesis, treatment appropriate Qi Yang Yin, Xie Fei Zhuyu. In order to further confirm the therapeutic effect of this prescription and further explore its possible mechanism of action, we carried out this study, that is, with the help of animal model of diabetic nephropathy. Objective: To observe the effects of Jiangtang Sanhuang Tablets on glucose and lipid metabolism, renal function, pathological changes of kidney tissue and microRNA-21 signaling pathway in early diabetic nephropathy rats. Methods: Eighty male SD rats were randomly divided into normal group (10 rats) and model group (70 rats) according to their body weight after one week of adaptive feeding. All rats were fed in a metabolic cage in the same animal room without insulin or other hypoglycemic drugs. After feeding for 3 weeks, blood glucose and urine volume were measured. If blood glucose was 16.7 mmol L-1, urine prouria was 150% and urine protein was measured for more than 30 mg in 24 hours. During the modeling period, 3 rats died, 3 blood glucose recovered, 8 rats with blood glucose up to the standard but urinary protein down to the standard, so 56 DN rats were established. 11 rats in the dosage group and 11 rats in the Irbesartan group were fed with clean general diet before and after modeling. The rats were fed and drinked freely during the experiment. The general condition of the rats was observed during the experiment. The body weight and FBG of the tail tip were measured every four weeks. The urine volume and water consumption were measured 24 hours after the last administration. The renal function (BUN, Scr), blood lipid (TC, TG, L) were measured at the end of the experiment. DL-C, HDL-C, HbA1c, 24-hour urinary protein (Upro); kidney of rats was taken out to calculate kidney weight, relative kidney weight; pathological morphology of rat kidney was observed by light and electron microscopy; TGF-beta 1, Smad3, Smad7 staining was observed by immunohistochemistry; TGF-beta 1, Smad3, Smad7 protein expression was detected by Western blotting; Results: 1. Body weight, water intake and urine volume: Body weight. After 4 and 8 weeks of drug intervention, the body weight of the drug intervention group increased significantly compared with the model group (P Compared with the model group, the middle dose group of Jiangtang Sanhuang Tablets and the high dose group of Jiangtang Sanhuang Tablets, the Irbesartan group decreased (P 0.01), while the low dose group of Jiangtang Sanhuang Tablets had no significant difference (P 0.05). There was no significant difference in the middle dose group of Tangsanhuang Tablets (P 0.05), but the high dose group of Jiangtangsanhuang Tablets was significantly less than that of Irbesartan Tablets (P 0.01). The urine volume of the high dose group of Jiangtang Sanhuang Tablets decreased (P 0.05), but the middle dose group of Jiangtang Sanhuang Tablets had no difference (P 0.05). The low dose group of Jiangtang Sanhuang Tablets was higher than the Irbesartan group (P 0.05). 2. Glucose and lipid metabolism: fasting blood glucose, after 4 weeks and 8 weeks of treatment, the low dose group of Jiangtang Sanhuang Tablets, the middle dose group of Jiangtang Sanhuang Tablets, the high dose group of Jiangtang Sanhuang Tablets Compared with the model group and irbesartan group (P 0.01), the glycosylated hemoglobin of the model group and irbesartan group was not significantly different (P 0.05). In the aspect of glycosylated hemoglobin, after 8 weeks of treatment, the low dose group of Jiangtang Sanhuang tablets, the middle dose group of Jiangtang Sanhuang tablets, the high dose group of Jiangtang Sanhuang tablets were significantly lower than the model group and irbesartan group (P 0.01). TC, TG, LDL-C were no difference (P 0.05). After 8 weeks of treatment, the low-dose group, middle-dose group and high-dose group of Jiangtang Sanhuang tablets were significantly lower than the model group and Irbesartan group (P 0.01). There was no difference between the model group and Irbesartan group (P 0.05). HDL-C, compared with the model group, the middle-dose group of Jiangtang Sanhuang tablets and the high-dose group of Jiangtang Sanhuang tablets were significantly lower than the model group. The kidney weight, relative kidney weight, renal function and urinary protein were significantly higher in the high dose group (P 0.01), but significantly lower in the low dose group (P 0.01) than in the model group (P 0.05). There was no significant difference between the low dose group and the model group (P 0.05), the middle dose group, the high dose group and the Irbesartan group (P 0.05), but the low dose group was significantly higher than the Irbesartan group (P 0.01). There was no significant difference between the high dose group and irbesartan group (P 0.05), but the low dose group was significantly higher than irbesartan group (P 0.01). The renal function (BUN, Scr), the drug intervention group was significantly lower than the model group (P 0.01), the high dose group of Jiangtang Sanhuang tablets was no significant difference compared with irbesartan group (P 0.05), and the low dose group was significantly higher than irbesartan group (P 0.05). There was no significant difference in urinary protein between the model group and the drug intervention group before treatment (P 0.05). After 8 weeks of treatment, compared with the model group, the low dose group of Jiangtang Sanhuang tablets decreased (P 0.05), the middle dose group of Jiangtang Sanhuang tablets and the high dose group of Jiangtang Sanhuang tablets decreased (P 0.05). Compared with irbesartan group, there was no significant difference (P 0.05) in the high-dose group of Jiangtang Sanhuang Tablets, the low-dose group of Jiangtang Sanhuang Tablets, and the middle-dose group of Jiangtang Sanhuang Tablets were significantly higher than that of irbesartan group (P 0.01). In type I group, the kidney lesions were serious. The glomerulus enlarged obviously, the glomerulus swelled and congested, the renal vesicle narrowed, the glomerular mesangial cells proliferated, some renal tubular cells hypertrophy, some vacuoles degenerated, the capillary lumen narrowed, the foot process flattened, the structure unclear, mitochondrial vacuole-like change, the increase of mesangial matrix, the renal tubular epithelial cells. Low-dose Jiangtang Sanhuang Tablets group, middle-dose Jiangtang Sanhuang Tablets group, high-dose Jiangtang Sanhuang Tablets group, irbesartan group can improve the renal pathological changes of DN, of which high-dose Jiangtang Sanhuang Tablets group has the best effect. 5. Expression of TGF-beta 1, Smad3, Smad7 protein in kidney: Immunohistochemical staining results showed that compared with normal group, model group T GF-beta 1, Smad3 protein expression increased significantly (P 0.01), showing brown-yellow granules, very deep coloring, drug intervention group between the normal group and the model group, significantly lower than the model group (P 0.01); compared with Irbesartan group, high-dose Jiangtang Sanhuang tablets group had no significant difference (P 0.05), low-dose Jiangtang Sanhuang tablets group, middle-dose Jiangtang Sanhuang tablets group was higher than Irbesartan group. Compared with the model group, the expression of Smad7 in the drug intervention group was significantly increased (P 0.01); the expression of Smad7 in the Irbesartan group was significantly higher than that in the low-dose group, the middle-dose group and the high-dose group (P 0.01). The expression of TGF-beta 1, Smad3 and Smad7 protein in the model group was measured by Western blotting. The expression of TGF-beta 1 and Smad3 protein in the high-dose group was not significantly different from that in the Irbesartan group (P 0.05). Compared with the normal group, the expression of Smad7 protein in the model group was significantly decreased (P 0.01), that in the drug intervention group was significantly higher than that in the model group (P 0.01), that in the Irbesartan group was significantly higher than that in the low dose group, and that in the middle dose group (P 0.01). There was no significant difference in TGF-1, Smad3, Smad7, microRNA-21 mRNA expression between high-dose Jiangtang Sanhuang Tablets group and control group (P 0.05). RTQ-PCR assay showed that TGF-1, Smad3, microRNA-21 mRNA expression in the kidney of rats was significantly higher in model group than in model group (P 0.01). There was no significant difference between the high-dose group and irbesartan group (P 0.05), but the low-dose group of Jiangtang Sanhuang tablets and the middle-dose group of Jiangtang Sanhuang tablets were significantly higher than that of irbesartan group (P 0.01). There was no significant difference between the dosage group and irbesartan group (P 0.05), but the low dosage group of Jiangtang Sanhuang tablets and the middle dosage group of Jiangtang Sanhuang tablets were significantly lower than that of irbesartan group (P 0.01). Conclusion: 1. On the basis of summing up the etiology, pathogenesis and treatment of diabetic nephropathy, the pathogenesis of diabetic nephropathy is a mixture of deficiency and excess. It can effectively prevent and treat DN rats. 2. Jiangtang Sanhuang tablets can improve the general state of DN rats, reduce blood sugar and regulate blood lipids. 3. Jiangtang Sanhuang tablets can reduce urinary protein of DN rats, reduce serum BUN and Scr, and protect the kidney of DN rats to a certain extent. 4. Jiangtang Sanhuang Tablet can improve the pathological damage of kidney tissue in DN rats, and can delay the pathological damage of kidney to some extent. 5. Decrease
【學(xué)位授予單位】：廣州中醫(yī)藥大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R285.5

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