本文選題：KLF4 + 2型糖尿病腎病��； 參考：《河北醫(yī)科大學(xué)》2017年碩士論文

【摘要】：目的:糖尿病腎病(diabetic nephropathy,DN)是2型糖尿病的嚴(yán)重并發(fā)癥。研究DN時蛋白尿的發(fā)生發(fā)展機(jī)制,對于預(yù)防DN,以及采取針對性的措施延緩DN的發(fā)展,從而提高2型糖尿病患者的生活質(zhì)量和生活水平有著重要臨床和社會意義。2型糖尿病時,足細(xì)胞之間的裂隙(slit diaphragm,SD)結(jié)構(gòu)消失,足突融合(foot process effacement),最終導(dǎo)致蛋白尿的發(fā)生。足細(xì)胞裂孔膜上的nephrin、CD2AP,足細(xì)胞足突上的α-actin4,足細(xì)胞和腎小球基底膜之間的integrinβ1等蛋白分子的丟失都會造成足細(xì)胞損傷,導(dǎo)致蛋白尿的發(fā)生。Krüppel樣轉(zhuǎn)錄因子(krüppel-like factors,KLFs)屬于核轉(zhuǎn)錄因子超家族,調(diào)節(jié)細(xì)胞的多種生物過程,包括增殖、分化、生長、發(fā)育。近年來的研究發(fā)現(xiàn),KLF4在腎臟的發(fā)育和維持其正常生理功能中也具有重要的作用。我們在前期的實(shí)驗(yàn)中,發(fā)現(xiàn)2型糖尿病小鼠腎臟中KLF4的mRNA的表達(dá)水平顯著下降。結(jié)果初步提示,KLF4可能與2型糖尿病腎病的發(fā)生有關(guān)。阿霉素(adriamycin,ADM)誘導(dǎo)的腎病小鼠的尿蛋白水平顯著升高,同時足細(xì)胞中,KLF4和nephrin的表達(dá)也是顯著降低的。相反,增加腎病小鼠足細(xì)胞中KLF4的表達(dá)又可以升高nephrin的表達(dá),降低尿蛋白水平。那么KLF4表達(dá)下降是否與2型糖尿病腎病蛋白尿的發(fā)生有關(guān)?其機(jī)制如何?針對這一問題,本實(shí)驗(yàn)以2型糖尿病的db/db小鼠以及高脂環(huán)境中的足細(xì)胞作為實(shí)驗(yàn)對象,研究KLF4在2型糖尿病腎病蛋白尿發(fā)生中的作用及其機(jī)制,為認(rèn)識2型糖尿病腎病蛋白尿發(fā)生的分子機(jī)制提供實(shí)驗(yàn)數(shù)據(jù)。方法:1實(shí)驗(yàn)動物采用db/db小鼠作為2型糖尿病動物模型,用尾靜脈注射過表達(dá)KLF4腺病毒(Ad-GFP-KLF4)的方法改變db/db小鼠腎內(nèi)KLF4的表達(dá)水平。2細(xì)胞株條件性永生化小鼠足細(xì)胞。用棕櫚酸(c16:0)模擬2型糖尿病的高脂環(huán)境。用過表達(dá)klf4腺病毒感染足細(xì)胞,改變klf4的表達(dá)水平。3標(biāo)本收集分別于第8周、12周、16周收集尿液并取腎臟組織。腎臟組織分別用于westernblot、pcr、pas染色、免疫組化實(shí)驗(yàn)等。4細(xì)胞收集對數(shù)生長期足細(xì)胞經(jīng)相應(yīng)濃度bsa、c16:0、c16:0+ad-gfp、c16:0+ad-gfp-klf4處理48小時后,收集細(xì)胞進(jìn)行westernblot及pcr分析實(shí)驗(yàn)。5lowrry法測定小鼠24小時尿蛋白總量。6實(shí)時定量pcr檢測klf4在2型糖尿病小鼠腎臟中的mrna表達(dá)水平,檢測nephrin和integrinβ1在高脂環(huán)境小鼠足細(xì)胞的mrna表達(dá)水平。7westernblot檢測klf4在2型糖尿病小鼠腎臟中的蛋白表達(dá)水平,以及klf4、nephrin、α-actin4和integrinβ1在高脂環(huán)境小鼠足細(xì)胞的蛋白表達(dá)水平。8pas染色觀察小鼠腎臟腎小球結(jié)構(gòu)9免疫組織化學(xué)分析2型糖尿病小鼠腎小球中nephrin、cd2ap、α-actin4、integrinβ1和integrinα3的蛋白表達(dá)水平。10數(shù)據(jù)處理采用spss17.0軟件進(jìn)行統(tǒng)計(jì)學(xué)處理分析,對所測定結(jié)果進(jìn)行正態(tài)性及方差齊性檢驗(yàn),數(shù)據(jù)用x±sd表示,兩組間比較用雙尾-t檢驗(yàn)分析。p0.05為差異有顯著性意義。結(jié)果:1klf4在db/db小鼠腎小球中表達(dá)下降1.12型糖尿病小鼠的尿蛋白水平與同周齡的對照組db/m小鼠(8周:5037.34±1037.73μg/24h;12周:2649.32±87.07μg/24h;16周:34605.02±16160.58μg/24h)相比,db/db小鼠在第8周(4777.18±1378.49μg/24h)時尿蛋白水平?jīng)]有明顯的變化,但隨著周齡的增加,在第12周(18629.52±3885.96μg/24h,p0.01)和第16周(323798.60±67766.10μg/24h,p0.01)尿蛋白水平逐漸增高,顯著高于對照組。1.2klf4在腎小球中的表達(dá)水平pcr的結(jié)果顯示,與對照組db/m小鼠相比,db/db小鼠腎皮質(zhì)中klf4的mrna表達(dá)水平顯著下降。westernblot的結(jié)果顯示,與對照組db/m小鼠相比,db/db小鼠腎皮質(zhì)中klf4蛋白表達(dá)水平顯著下降。免疫組化的結(jié)果顯示,與對照組db/m小鼠(275.50±30.26)相比,db/db小鼠(150.25±15.97,p0.01)腎小球中klf4表達(dá)水平顯著下降。以上結(jié)果提示,腎小球klf4表達(dá)下降可能與2型糖尿病腎病蛋白尿的發(fā)生有關(guān)。2腎小球過表達(dá)klf4后,db/db小鼠的尿蛋白水平顯著降低2.1klf4在腎小球中的表達(dá)水平免疫組化的結(jié)果顯示,與無過表達(dá)klf4的db/db小鼠(152.25±12.89)相比,過表達(dá)klf4的db/db小鼠腎小球中klf4表達(dá)水平(317.5±33.25,p0.01)顯著上調(diào)。2.2腎小球過表達(dá)klf4后,db/db小鼠的尿蛋白水平過表達(dá)klf4后,db/db小鼠尿蛋白水平(264330.80±33824.15μg/24h,p0.05)較無過表達(dá)klf4的對照組(435255.6±10446.17μg/24h)明顯降低。以上結(jié)果說明,腎小球klf4表達(dá)下降,是2型糖尿病腎病蛋白尿發(fā)生的原因之一,增加klf4的表達(dá)能夠改善2型糖尿病腎病尿蛋白。3klf4可通過增加db/db小鼠腎小球中nephrin、integrinβ1和α-actin4的表達(dá)來改善2型糖尿病腎病的尿蛋白水平3.12型糖尿病小鼠腎小球的結(jié)構(gòu)pas染色結(jié)果顯示db/db小鼠與對照組db/m小鼠的腎小球結(jié)構(gòu)沒有明顯差異。3.2腎小球蛋白濾過屏障關(guān)鍵蛋白,nephrin、integrinβ1、integrinα3、α-actin4和cd2ap的表達(dá)水平免疫組化的結(jié)果顯示,除cd2ap和integrinα3外,db/db小鼠腎小球中nephrin(0.148±0.003,p0.01)、integrinβ1(0.109±0.009,p0.05)和α-actin4(0.136±0.001,p0.05)的表達(dá)水平均顯著低于對照組db/m小鼠(nephrin:0.208±0.016;integrinβ1:0.180±0.008;α-actin4:0.159±0.007);當(dāng)db/db小鼠過表達(dá)klf4后,腎小球中nephrin(0.178±0.006,p0.01)、integrinβ1(0.164±0.006,p0.01)和α-actin4(0.156±0.006,p0.05)的表達(dá)水平顯著高于無過表達(dá)klf4的db/db小鼠(nephrin:0.148±0.003;integrinβ1:0.109±0.009;α-actin4:0.136±0.001)。與文獻(xiàn)報(bào)道相符,integrinβ1、integrinα3、α-actin4和cd2ap在腎小管中也有表達(dá)。與對照組db/m小鼠相比,db/db小鼠腎小管中α-actin4的表達(dá)較低,integrinβ1、integrinα3、和cd2ap的表達(dá)無明顯的差異;db/db小鼠過表達(dá)klf4后,腎小管中integrinβ1、integrinα3、α-actin4和cd2ap的表達(dá)無明顯的變化。nephrin特異性表達(dá)在腎小球中,但在本實(shí)驗(yàn)中,在腎小管中也有少量陽性顆粒,可能是因?yàn)閷?shí)驗(yàn)條件不夠優(yōu)化所致。以上結(jié)果說明,2型糖尿病小鼠腎小球中nephrin、integrinβ1和α-actin4的表達(dá)水平與klf4的表達(dá)水平有關(guān),低表達(dá)水平的klf4有可能通過影響nephrin、integrinβ1和α-actin4的表達(dá)下降而與2型糖尿病腎病蛋白尿的發(fā)生相關(guān)聯(lián)。另外,2型糖尿病腎病蛋白尿的發(fā)生可能還與腎小管中α-actin4的表達(dá)下降有關(guān)。4在高脂環(huán)境的足細(xì)胞中,klf4可以調(diào)節(jié)nephrin、integrinβ1的表達(dá)在不同濃度的c16:0環(huán)境下,足細(xì)胞中klf4呈濃度依賴性下降。并且發(fā)現(xiàn),足細(xì)胞在c16:0濃度為250μm的高脂環(huán)境中48小時后,伴隨著klf4的下降,nephrin和integrinβ1蛋白表達(dá)水平均顯著下降,而α-actin4的蛋白表達(dá)水平?jīng)]有明顯的變化;對高脂環(huán)境的足細(xì)胞過表達(dá)klf4后,nephrin的mrna和蛋白表達(dá)水平顯著升高;integrinβ1的mrna表達(dá)水平無明顯的變化,蛋白表達(dá)水平顯著升高。此結(jié)果說明,在高脂環(huán)境的足細(xì)胞中,klf4很可能從轉(zhuǎn)錄水平調(diào)節(jié)了nephrin的表達(dá),進(jìn)而上調(diào)了蛋白的表達(dá);從尚未知的途徑只影響了integrinβ1的蛋白表達(dá)。以上結(jié)果說明,2型糖尿病腎病蛋白尿的發(fā)生與klf4表達(dá)減少有關(guān)。其可能機(jī)制:(1)與足細(xì)胞中低水平klf4轉(zhuǎn)錄調(diào)節(jié)nephrin的表達(dá)下降有關(guān);(2)與足細(xì)胞中低水平klf4通過未知途徑使integrinβ1表達(dá)下降有關(guān)。結(jié)論:足細(xì)胞中klf4表達(dá)下降,進(jìn)而使nephrin表達(dá)降低,導(dǎo)致了2型糖尿病腎病蛋白尿的發(fā)生。上調(diào)足細(xì)胞中KLF4的表達(dá),可以減少蛋白尿。
[Abstract]:Objective: diabetic nephropathy (DN) is a serious complication of type 2 diabetes. The study of the pathogenesis of proteinuria in DN, for the prevention of DN, and to take specific measures to delay the development of DN, so as to improve the quality of life and the living level of type 2 diabetes patients have important clinical and social significance of.2 type diabetes, The slit diaphragm (SD) structure between the podocytes disappears and the foot process fusion (foot process effacement) leads to the occurrence of proteinuria. The nephrin, CD2AP, the alpha -actin4 on the foot cell of the podocytes, the loss of the integrin beta 1 and other protein molecules between the podocytes and the basement membrane of the glomeruli will cause the foot cell damage and lead to the injury of the podocyte. The occurrence of.Kr u ppel like transcription factor (KR u ppel-like factors, KLFs) is a nuclear transcription factor superfamily, which regulates a variety of biological processes in cells, including proliferation, differentiation, growth, and development. Recent studies have found that KLF4 also plays an important role in the development of the kidney and the maintenance of its normal physiological functions. It was found that the expression level of KLF4 mRNA in the kidneys of type 2 diabetic mice decreased significantly. The results suggested that KLF4 may be associated with the occurrence of type 2 diabetic nephropathy. The urinary protein level of nephrotic mice induced by adriamycin (adriamycin, ADM) was significantly increased, and the expression of KLF4 and nephrin in the podocytes was also significantly reduced. The expression of KLF4 in the podocytes of nephrotic mice can also increase the expression of nephrin and reduce the level of urinary protein. Is the decline of KLF4 expression related to the pathogenesis of type 2 diabetic nephropathy? How is the mechanism of this problem? In this study, the experiment was conducted on the db/db mice of type 2 diabetes mellitus and the podocytes in the high fat environment as the experimental object. The role of KLF4 in the pathogenesis of type 2 diabetic nephrotic proteinuria and its mechanism provide experimental data for understanding the molecular mechanism of proteinuria in type 2 diabetic nephropathy. Method: 1 experimental animals used db/db mice as animal model of type 2 diabetes mellitus, and KLF4 adenovirus (Ad-GFP-KLF4) was injected into the tail vein to change the kidney of db/db mice. KLF4 expression level.2 cell line conditioned immortalized mouse foot cells. Use palmitic acid (c16:0) to simulate the high fat environment of type 2 diabetes. Using KLF4 adenovirus to infect podocytes, and change the expression level of KLF4,.3 specimens were collected for eighth weeks, 12 weeks, 16 weeks to collect urine and take kidney tissue. The renal tissue was used for Westernblot, PCR, respectively. PAS staining, immunohistochemistry and other.4 cells collected logarithmic growth stage podocytes for 48 hours after the corresponding concentration of BSA, c16:0, c16:0+ad-gfp, c16:0+ad-gfp-klf4, and collected cells for Westernblot and PCR analysis experiments..5lowrry method was used to determine the total amount of 24 hour urine protein in mice and.6 real time PCR detection KLF4 was in the kidney of type 2 diabetic mice. Na expression level, detection of mRNA expression level of nephrin and integrin beta 1 in high fat environment mouse foot cells.7westernblot detection KLF4 in type 2 diabetic mice kidney protein expression level, and KLF4, nephrin, alpha -actin4 and integrin beta 1 in the high fat environment mouse foot cells egg white expression level.8pas staining mouse kidney glomeruli Structure 9 immunohistochemical analysis of the protein expression level of nephrin, CD2AP, alpha -actin4, integrin beta 1 and integrin alpha 3 in the glomeruli of type 2 diabetic mice. The.10 data processing was analyzed by SPSS17.0 software. The results were tested with normality and homogeneity of variance. The data were expressed in X + SD, and the two groups were compared with double tail -t. The test and analysis of.P0.05 showed significant difference. Results: 1klf4 was expressed in db/db mice glomeruli to decrease the urine protein level of type 1.12 diabetic mice and db/m mice of the same week age group (8 weeks: 5037.34 + 1037.73 mu g/24h; 12 weeks: 2649.32 + 87.07 mu g/24h; 16 weeks: 34605.02 + 16160.58 Mu g/24h), db/db mice in eighth weeks (4777.18 + 1) There was no significant change in urine protein level at 378.49 g/24h), but with the increase of week age, the level of urine protein increased gradually at twelfth weeks (18629.52 + 3885.96, P0.01) and sixteenth weeks (323798.60 + 67766.10, g/24h, P0.01), which was significantly higher than that of.1.2klf4 in the small kidney balls of the control group. The result showed that it was with the control group of db/m mice. The mRNA expression level of KLF4 in the renal cortex of db/db mice decreased significantly by.Westernblot, and the results showed that the expression of KLF4 protein in the renal cortex of db/db mice decreased significantly compared with the control group db/m mice. The results of immunohistochemistry showed that compared with the control group db/m mice (275.50 + 30.26), db/db mice (150.25 + 15.97, P0.01) were KLF4 in the glomeruli. The above results suggest that the decrease of KLF4 expression in glomeruli may be related to the occurrence of.2 glomerular overexpression of KLF4 in type 2 diabetic nephropathy. The urinary protein level in db/db mice significantly decreased the expression level of 2.1klf4 in the glomeruli, and the db/db mice without overexpression of KLF4 (152.25 + 12) .89) compared with the expression level of KLF4 in the glomeruli of db/db mice expressing KLF4 (317.5 + 33.25, P0.01), the.2.2 glomerular overexpression KLF4 was significantly up-regulated, and the urine protein level of db/db mice was overexpressed in KLF4, and the urinary protein level of db/db mice (264330.80 + 33824.15 mu g/24h, P0.05) was significantly higher than that of the control group (435255.6 + 10446.17 mu). These results suggest that the decrease of KLF4 expression in glomeruli is one of the causes of proteinuria in type 2 diabetic nephropathy. The increase of KLF4 expression can improve the urinary protein.3klf4 of type 2 diabetic nephropathy, which can improve the urinary protein level of type 2 diabetic nephropathy by increasing nephrin, integrin beta 1 and alpha -actin4 in the glomeruli of mice. The glomerular structure PAS staining results showed that the glomerular structure of db/db mice and the control group db/m mice had no significant difference in the.3.2 glomerular protein filter barrier key protein, nephrin, integrin beta 1, integrin alpha 3, alpha -actin4 and CD2AP expressed in the immunohistochemical results, except CD2AP and integrin alpha 3, db/db mice. The expression level of nephrin (0.148 + 0.003, P0.01) in glomeruli, integrin beta 1 (0.109 + 0.009, P0.05) and alpha -actin4 (0.136 + 0.001, P0.05) were significantly lower than that of the control group db/m mice (nephrin:0.208 + 0.016; integrin beta 1:0.180 + 0.008; alpha -actin4:0.159 + 0.007). The expression level of RIN beta 1 (0.164 + 0.006, P0.01) and alpha -actin4 (0.156 + 0.006, P0.05) was significantly higher than that of db/db mice without overexpression of KLF4 (nephrin:0.148 + 0.003; integrin beta 1:0.109 + 0.009; alpha -actin4:0.136 + 0.001). The same as the literature reported, integrin beta 1, integrin alpha 3, and the expression in renal tubules. In contrast, the expression of alpha -actin4 in the renal tubules of db/db mice was lower, integrin beta 1, integrin alpha 3, and CD2AP expression were not significantly different. After db/db mice overexpressed KLF4, the expression of integrin beta 1, integrin alpha 3, alpha -actin4 and CD2AP in renal tubules had no significant changes in the glomeruli, but in this experiment, the renal tubules were also in the renal tubules. The results suggest that the expression level of nephrin, integrin beta 1 and alpha -actin4 in the glomeruli of type 2 diabetic mice is related to the level of KLF4 expression. The low expression level of KLF4 may be associated with the decrease of the expression of nephrin, integrin beta 1, and alpha -actin4 and type 2 diabetes. In addition, the occurrence of proteinuria in type 2 diabetic nephropathy may also be associated with a decrease in the expression of alpha -actin4 in renal tubules related to.4 in the hyperlipidemic podocytes, KLF4 can regulate nephrin, the expression of integrin beta 1 in the c16:0 environment of different concentrations, KLF4 in a concentration dependent decrease in the podocytes, and found, After 48 hours in the high fat environment with the concentration of 250 c16:0 m, the expression level of nephrin and integrin beta 1 protein was significantly decreased with the decrease of KLF4, while the protein expression level of alpha -actin4 was not significantly changed; the mRNA and protein expression level of nephrin was significantly increased after the hyperlipidemic podocyte KLF4 was overexpressed; integrin beta 1. There is no obvious change in the expression level of mRNA and a significant increase in protein expression level. This results suggest that in the hyperlipidemic podocytes, KLF4 is likely to regulate the expression of nephrin from the transcriptional level, and then up-regulated the expression of the protein; the unknown pathway only affects the protein expression of integrin beta 1. The above results indicate that type 2 diabetic nephropathy is indicated. The occurrence of proteinuria is related to the decrease of KLF4 expression. The possible mechanism is: (1) it is related to the decline in the expression of low level KLF4 transcriptional regulation of nephrin; (2) the low level of KLF4 in the Poda is associated with the decline in the expression of integrin beta 1 in the unknown pathway. Conclusion: the KLF4 table in the podocytes decreases, and the expression of nephrin is reduced, resulting in type 2 diabetes. The onset of proteinuria in patients with disease nephropathy can increase proteinuria by up regulating the expression of KLF4 in podocytes.
【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R587.2;R692.9

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