银杏叶对单侧输尿管梗阻大鼠肾小管上皮细胞转分化的影响

肾间质纤维化是所有肾病进行性发展的最终通路,是导致终末期肾病的主要病理基础。目前研究发现,肾小管上皮转分化在肾间质纤维化的发生、发展过程中发挥重要作用。肾小管上皮在转分化过程中逐步失去其原有特征而获得肌成纤维细胞的特征,如表达α-平滑肌肌动蛋白(α-SMA),并合成细胞外基质,转化生长因子-β1(TGF-β1)被认为参与了这一过程并在其中起着十分关键的作用[1]。探索有效抑制和逆转转分化的发生,从而抑制肾间质纤维化的进展具有重要意义。本实验采用大鼠单侧输尿管结扎术(UUO)建立肾间质纤维化动物模型,用银杏叶进行治疗,选用公…     

干细胞治疗梗阻性肾病:研究现状与存在问题

背景:梗阻性肾纤维化的治疗思路主要集中于解除肾结石、肾盂输尿管狭窄等危险因素以及针对上皮-间质转化、肾纤维化发生相关因子及改善肾间质微循环等肾纤维化发生机制进行,目前治疗效果并不理想。以干细胞为基础的再生医学研究有可能为梗阻性肾纤维化的治疗带来新的希望。目的:综合分析不同来源干细胞治疗梗阻性肾纤维化的机制及研究进展。方法:检索Pub Med、Ovid medline全文数据库、CNKI、维普数据库、万方数据库等并收集关于干细胞治疗梗阻性肾纤维化的文章,中文以"干细胞、梗阻性肾病、肾纤维化"为检索词,英文以"stem cells、obstructive nephropathy、renal fibrosis"为检索词进行检索,最终选择51篇文章进行总结。结果与结论:干细胞治疗梗阻性肾病尚处于实验阶段,大量研究表明干细胞移植对梗阻性肾病肾间质纤维化的治疗具有积极的作用,干细胞可移植定位于肾间质,向肾小管上皮细胞分化,促进肾纤维化的恢复,干细胞还能分泌、上调或下调一些细胞因子抗纤维化,在及时、早期解除梗阻的前提下,干细胞移植有可能为梗阻性肾纤维化恢复提供一种新型的治疗方案。     

IgA肾病患者肾间质肥大细胞浸润的临床意义

目的 研究肥大细胞（MC）在IgA肾病患者肾间质中的分布及间质纤维化的关系。方法 采用甲苯蓝特殊染色法及MC特异酶（即类酶蛋白酶,tryptase）免疫组化染色法,对12例IgA肾病患者肾活检标本中的MC进行了观察。结果 （1）肾脏皮、髓质均可见到MC,多见于纤维化区域、血管周围、萎缩或扩张小管周围及肾小球周围。（2）系膜细胞的增殖程度与MC数无关,而随着IgA肾病患者MC的数增加,间质纤维化加重,差异显著（P＜0．05）。结论 IgA肾病患者的肾间质中存在MC,并与肾间质的纤维化有关。     

肾纤维化源性成纤维细胞增殖能力的初步研究

目的:探讨肾间质纤维化的机理。方法:建立单侧输尿管结扎所致肾间质纤维化模型,以MTT比色法观察病变肾间质成纤维细胞的增殖能力。结果:纤维化动物模型肾小管间质的改变,于术后第3天出现小管扩张,间质内淋巴细胞和单核细胞浸润;第8天出现纤维素沉积,且随着时间的延长,间质细胞浸润和间质纤维化逐渐加重。肾小球的改变较晚,随着结扎手术时间的延长,源于病变肾组织的肾间质成纤维细胞的增殖能力逐渐增强,明显的增殖出现于术后第8天组的细胞及以后的细胞组。结论:肾间质纤维化的程度与成纤维细胞的增殖能力相一致。     

巨噬细胞在肾间质纤维化中的研究进展

肾间质纤维化(Renal interstitial fibrosis,RIF)是一种多病因的慢性肾脏疾病,其病程的持续发展最终导致终末期肾病。巨噬细胞作为肾间质纤维化发生过程中高度活跃的炎症性浸润细胞,近年来研究发现其能够以多种形式参与到纤维化的发展过程中,且呈现出错综复杂的作用机制,因此本文结合最新研究成果对巨噬细胞在肾间质纤维化中的功能作用进行综述。     

甘草酸18α体对梗阻性肾病大鼠肾间质中NF-κB表达的影响

目的 :探讨甘草酸 18α体对梗阻性肾病大鼠肾间质中NF κB表达的影响。方法 :结扎大鼠单侧输尿管建立梗阻性肾病模型。分别于术后 7、14、2 8d和 5 6d处死实验动物 ,切取肾皮质部位组织 ,用光镜、电镜观察肾间质的病理形态学变化 ;用免疫组织化学染色检测肾间质中NF κB和Ⅲ型胶原蛋白的表达 ,并用EIG综合图象分析系统对其表达进行半定量分析。结果 :模型显示肾间质呈进行性纤维化。半定量分析发现 ,手术后 7d ,甘草酸治疗组和预防组与假手术组相比较 ,肾间质中NF κB和Ⅲ型胶原蛋白的表达呈进行性的显著增多(P <0 .0 1) ,与生理盐水组相比较呈进行性的显著减少 (P <0 .0 1) ,但甘草酸治疗组和预防组之间无明显差异 (P >0 .0 5 )。结论 :甘草酸可能通过下调梗阻性肾病大鼠肾间质中NF κB的表达 ,抑制肾间质纤维化的发生     

肥大细胞在腺嘌呤致慢性肾功能衰竭模型大鼠肾组织中的浸润

背景：近年研究提示肥大细胞的浸润与人类多种肾病患者的肾间质纤维化关系密切。肥大细胞是否参与了腺嘌呤致慢性肾功能衰竭大鼠模型肾间质纤维化？作者未检索到此类报道。 目的：探讨肥大细胞在腺嘌呤致慢性肾功能衰竭大鼠模型肾组织中的分布特点及其与肾间质纤维化之间的关系。 方法：46只雄性Wistar大鼠,随机分成对照组和模型组。模型组予腺嘌呤灌胃,剂量为150 mg/(kg•d);对照组以等量生理盐水灌胃。分别于不同时间点检测血尿指标,并对肾组织进行苏木精-伊红染色、Masson染色及肾小管间质纤维化评分;采用甲苯胺蓝和免疫组化方法观察肥大细胞在肾脏的分布及浸润数量,并分析它们与肾间质纤维化的相关性。 结果与结论：模型组大鼠随着灌胃时间的延长,尿蛋白/ 尿肌酐、血清肌酐和血清尿素氮持续升高,肾间质纤维化评分也逐渐增加,不同时间点之间及其与对照组比较,差异均有显著性意义(P < 0.01);肥大细胞主要分布在模型鼠的肾小管间质、肾小球囊外及血管周围,间质纤维化较重区域浸润较多,其浸润数量随着模型鼠肾损害的加重逐渐增加,不同时间点之间比较,差异均有显著性意义(P < 0.01),并且与肾间质纤维程度呈显著正相关(r =0.96,P < 0.001)。提示肥大细胞可能促进了腺嘌呤致慢性肾功能衰竭大鼠模型肾间质纤维化的进展。     

肾纤维化手术动物模型构建及相关机制研究进展

慢性肾疾病发展到一定阶段可引起肾纤维化。肾纤维化可由多种因素诱导产生,包括肾受到严重创伤和感染,肾血液循环阻塞或者免疫反应等。各种因素引起肾组织受损后,大量胶原纤维在间质沉积,瘢痕形成,导致肾结构和功能发生改变,从而引起肾纤维化。迄今关于肾纤维化的发生机制尚不完全明确,而理想的肾纤维化模型对于肾纤维化的机制研究具有重要意义。目前很多关于肾纤维化的研究是通过手术的方式建立肾纤维化的动物模型。因此本文主要总结了近年来关于肾纤维化手术模型的构建方法及肾纤维化的发病机制。     

血管内皮生长因子在梗阻性肾病大鼠肾间质纤维化中的变化

血管内皮生长因子(vascular endothelial growth factorVEGF)是一种多功能细胞因子。目前认为VEGF与糖尿病肾病蛋白尿的形成有关,在5/6肾切除大鼠外源性VEGF具有保护肾功能的作用。本实验利用大鼠单侧输尿管结扎(UUO)模型观察VEGF在肾间质纤维化中的变化。1材料与方法1.1实验动     

缬沙坦降低糖尿病大鼠肾细胞增殖和NF-κB表达

血管紧张素II受体I拮抗剂(angiotensin II receptorⅠan-tagonism,AT1Ra)通过受体途径阻断肾素-血管紧张素系统(Renin-Angiotensin system,R-A系统),具有肾保护作用,但其作用机制尚未完全阐明。研究表明,糖尿病早期肾细胞异常增生造成了糖尿病肾病的发生,导致后期肾小球硬化和肾间质纤维化[1]。本实验应用大鼠糖尿病模型,通过给予AT1Ra缬沙坦进行干预治疗,观察其对糖尿病大鼠肾细胞增殖及NF-κB的影响,以探讨其对肾脏的保护作用。1材料与方法1·1动物模型及分组:选取体重230~250 g的雄性SD大鼠30只(河北省实验动物中心提供),随机分…     

The pathogenesis of chronic renal failure

The pathogenesis of terminal renal failure is discussed. The following are distinguished: 1. Renal failure occurring against a background of decompensated benign nephrosclerosis, primary and secondary malignant nephrosclerosis, and stenosis of the renal artery. 2. Renal failure caused by loss of glomeruli. It is pointed out that in most glomerulopathies, including diabetic glomerulopathy and renal amyloidosis, terminal renal failure only develops when accompanying disease of the postglomerular vessels leading to interstitial fibrosis impairs the outflow of blood from the glomerulus to such an extent that no more urine is produced. 3. Renal failure in disease of the tubules themselves. It is emphasized that acute renal failure only becomes chronic when interstitial fibrosis develops from the interstitial edema occurring in the early stage of the disease. 4. Renal failure occurring in primary diseases of the renal cortical interstitium. The chronic sclerosing renal diseases arising from acute interstitial nephritis are dealt with, as also are reflux nephropathy, incomplete obstructive nephropathy, analgesic nephropathy, and chronic interstitial rejection reactions in transplanted kidneys.     

Interstitial myofibroblasts: predictors of progression in membranous nephropathy.

AIMS: To determine the role of interstitial myofibroblasts in the progression of membranous nephropathy; and to assess the predictive value of quantifying myofibroblasts in determining long term renal outcome. METHODS: All cases of membranous nephropathy, diagnosed by renal biopsy at University Hospital of South Manchester between 1984 and 1987, were studied retrospectively. The biopsy specimens (n = 26) were reviewed and analysed morphometrically to measure interstitial volume as a proportion of the total volume of renal cortex, and numbers of interstitial myofibroblasts (cells positive for alpha-smooth muscle actin within the interstitium). Clinical data, with a follow up of seven to eight years, was available for 24 patients, and renal outcome was correlated with pathological changes in the initial diagnostic biopsy specimen. RESULTS: The number of myofibroblasts and interstitial volume were inversely correlated with creatinine clearance at the initial biopsy, and at the end of follow up. Percentage sclerosed glomeruli or stage of glomerular disease, assessed by electron microscopy, did not correlate with renal function at initial biopsy or during follow up. The number of myofibroblasts, but not interstitial volume, correlated with severity of proteinuria at initial biopsy. Of 15 biopsy specimens showing no or mild interstitial fibrosis, four showed a notable increase in the number of interstitial myofibroblasts. All of these patients developed chronic renal failure, compared with three of 11 patients whose specimens showed no or a mild increase in myofibroblast numbers. CONCLUSIONS: Interstitial myofibroblasts play a role in the development of interstitial fibrosis and progressive renal failure in membranous nephropathy. Increased numbers of myofibroblasts in biopsy specimens showing only mild fibrosis may predict subsequent chronic renal failure.     

Congenital ureteropelvic junction obstruction: human disease and animal models

Ureteropelvic junction (UPJ) obstruction is the most frequently observed cause of obstructive nephropathy in children. Neonatal and foetal animal models have been developed that mimic closely what is observed in human disease. The purpose of this review is to discuss how obstructive nephropathy alters kidney histology and function and describe the molecular mechanisms involved in the progression of the lesions, including inflammation, proliferation/apoptosis, renin–angiotensin system activation and fibrosis, based on both human and animal data. Also we propose that during obstructive nephropathy, hydrodynamic modifications are early inducers of the tubular lesions, which are potentially at the origin of the pathology. Finally, an important observation in animal models is that relief of obstruction during kidney development has important effects on renal function later in adult life. A major short‐coming is the absence of data on the impact of UPJ obstruction on long‐term adult renal function to elucidate whether these animal data are also valid in humans.     

肾小球疾病间质泡沫细胞的分布及其临床病理意义

目的 观测肾间质泡沫细胞浸润常见的肾小球疾病临床类型与病理类型以及各种病理类型肾小球疾病间质泡沫细胞的分布特点及其与病理参数间的关系.方法 选取行肾活检的2 862患者为研究对象,观察间质泡沫细胞浸润常见的病理类型及泡沫细胞的分布特点.对诊断明确的Aplort综合征(Aplort syndrome,AS)5例、膜增生性肾小球肾炎(membranous proliferative glomerulonephritis,MPGN)28例、局灶节段硬化性肾小球肾炎(focal segmental glomerulosclerosis,FSGS) 144例、特发性膜性肾病(idiopathic membranous nephropathy,IMN) 132例和IgA肾病(Iga nephropathy,IgAN) 893例按间质是否存在泡沫细胞进行病理参数的比较.结果 (1)肾间质泡沫细胞浸润常见于AS患者;原发性肾小球疾病泡沫细胞浸润高发的病理类型依次为MPGN(46.43%)、FSGS(20.14%)、IMN(13.64%)、IgAN(6.27%).(2)间质泡沫细胞浸润组节段硬化发生率及比例显著高于无泡沫细胞组(P<0.05),其间质纤维化程度亦显著高于无泡沫细胞组(P<0.05).结论 肾间质泡沫细胞浸润常见于AS,但在MPGN、FSGS、IMN和IgAN患者中均可出现.肾间质泡沫细胞的浸润与间质纤维化、肾小球硬化有一定的关联.间质泡沫细胞的出现可能与肾组织慢性化病变形成有关.     

Transformation of interstitial fibroblasts and tubulointerstitial fibrosis in diabetic nephropathy

The developmental mechanism of tubulointerstitial fibrosis in diabetic nephropathy (DN) has not been elucidated. Tubulointerstitial fibrosis, as well as glomerulosclerosis, occurs in DN. Myofibroblasts which overproduce extracellular matrix are present in the renal interstitium in diabetics, although they are almost never seen in normal kidneys. The myofibroblasts appear to originate from interstitial fibroblasts. In addition, transforming growth factor-beta1 (TGF-beta 1), which can evoke myofibroblast transformation, is detected in interstitial cells in the diabetic kidney, but not in the normal kidney. Taken together, these findings led us to speculate that TGF-beta 1 induces the transformation of interstitial fibroblasts into myofibroblasts, followed by tubulointerstitial fibrosis. Based on this speculation, we discuss the developmental mechanism of tubulointerstitial fibrosis in this review.     

Chronic experimental hyperuricemic nephropathy.

Sustained, moderately severe hyperuricemia and severe uricosuria were produced in male Wistar rats by feeding dietary supplements of oxonic acid (0.4 gm. per day) and uric acid (0.6 gm per day). After 1 month, the kidneys showed the previously described histologic features of urate-blockade nephropathy characterized by intratubular deposits, tubular injury, and an exudative response consisting of neutrophilic granulocytes with early tophus formation. After 36 and 52 weeks of hyperuricemia, and with no gross evidence of renal failure, the kidneys showed a predominantly interstitial mononuclear cell infiltrate around regenerated tubules, an increase in interstitial fibrous tissue, infrequent renal tophi, and renal stones. The glomeruli and blood vessels appeared completely normal. There was no evidence of arthritis and no other target organ damage was detected. The chronic renal changes present in this animal model of induced hyperuricemia resemble those seen in human gouty nephropathy. The evolution of the experimental urate nephropathy observed during 1 year suggests that a primary acute inflammatory tubular injury is followed by a diffuse chronic interstitial nephritis and that the glomeruli and blood vessels are not primarily involved in the renal disease. This animal model may provide the opportunity to study factors influencing the renal sequelae of sustained hyperuricemia.     

Experimental analgesic nephropathy: changes in renal structure and urinary concentrating ability in Fischer 344 rats given continuous low doses of aspirin and paracetamol

Long-term treatment with aspirin and paracetamol produced renal papillary necrosis in female Fischer 344 rats. Aspirin (230 mg/kg body weight/day) and paracetamol (380 mg/kg body weight/day) were dissolved in drinking water and given continuously for up to 65 weeks. Renal morphological changes were examined between 21 weeks and 65 weeks of commencement of analgesic treatment using light and electron microscopy, and were compared with age-matched controls. Structural damage initially occurred in the mid-papillary region, and specifically involved the interstitial cells and interstitial matrix. Necrosis of the epithelium of the thin limbs of the loop of Henle was present only after interstitial changes were well established. Cortical interstitial fibrosis and tubular atrophy occurred after renal papillary changes were observed. There was no evidence of significant vascular damage. Urinary concentrating ability was measured sequentially during the period of analgesic treatment. A decrease in urine concentrating ability was present when early changes to the interstitial cells and matrix were observed, and concentrating ability continued to decrease in parallel with increasing morphological damage. This study describes an animal model of analgesic-induced nephropathy, enabling early morphological changes to be studied and correlated with renal functional changes.     

Prognostic significance of glomerular and tubulointerstitial morphometry in idiopathic membranous nephropathy

The purpose of our study was to investigate the prognostic value of clinical and pathological, in particular glomerular and tubulointerstitial morphometric variables in idiopathic membranous nephropathy (IMN). We prospectively followed 60 Caucasian patients diagnosed with idiopathic membranous nephropathy for at least 2 years or until primary outcome (≥50% permanent decrease in estimated glomerular filtration rate or death). Glomerular and tubulointerstitial morphometric variables at the time of renal biopsy were analyzed with respect to this outcome. Univariate analysis revealed that significant negative prognostic factors for this outcome were higher cholesterol and smaller albumin concentrations, higher creatinine and maximal 24-h proteinuria, higher grade of nephroangiosclerosis, higher glomerular basement membrane thickness and glomerulopathy index, higher interstitial fibrosis and tubular atrophy percentage and higher injury score. In multivariate analysis, only the maximal 24-h proteinuria and interstitial fibrosis and tubular atrophy percentage were independent predictors of this outcome. The results suggest that morphometric analysis, mainly quantitative measurement of interstitial fibrosis and tubular atrophy percentage, injury score, glomerular basement membrane thickness and glomerulopathy index could be used as an additional method for risk stratification of patients with idiopathic membranous nephropathy.