糖尿病肾病肾小球滤过膜结构与肾功能及代谢指标的关系

目的:观察2型糖尿病肾病(T2DN)患者肾小球滤过膜超微结构改变与肾功能及代谢指标的关系.方法:将明确诊断的T2DN 75例患者分为:微量白蛋白尿组(尿白蛋白/24h 30～300 mg);蛋白尿组(尿蛋白0.5～2.0g/24h)和大量蛋白尿组(尿蛋白＞3.5g/24h).收集三组患者临床指标,并分别使用Cockcroft-Gault公式、简化的肾脏疾病饮食控制(MDRD)公式等计算患者的肾小球滤过率(eGFR);采用形态学计量分析方法分别测算肾小球体积、肾小球足细胞和内皮细胞的相对密度、绝对数目和足细胞足突宽度及肾小球基膜(GBM)厚度.结果:(1)肾小球滤过膜结构与GFR的关系:微量白蛋白尿组Ccr与肾小球足细胞密度及数日均负相关(分别为r=-0.480,P＜=0.05;r=-0.478,P＜0.05);大量蛋白尿组以SCr估算的eGFR与肾小球足细胞密度正相关(r=0.462,P＜0.05);余均未见明显相关.(2)多元回归分析结果:微量白蛋白尿组中肾小球足细胞密度、糖化血红蛋白、三酰甘油、尿酸与Ccr相关(R~2=0.616,P＜0.01);大量蛋白尿组肾小球足细胞密度、尿酸与以SCr估算的eGFR相关(R~2=0.613,P＜0.01).(3)肾小球滤过膜结构及肾小球体积与糖、脂质代谢指标的关系:①肾小球体积与血糖的关系:微量白蛋白尿组中肾小球体积和糖化血红蛋白正相关(r=0.425,P＜0.05);而在蛋白尿组则为负相关(r=-0.427,P＜0.05).②GBM厚度与血糖、血脂代谢指标的关系:微量白蛋白尿组中,以GBM厚度为因变量,糖及脂质代谢水平为自变量,可见空腹血糖水平和总胆固醇与基膜厚度相关(R~2=0.247,P＜0.05).结论:肾小球滤过膜结构与GFR及糖、脂质代谢水平间存在着密切联系,且与DN发展的不同阶段相关.     

糖尿病肾病患者足细胞病变的临床病理特征

目的：研究2型糖尿病肾病患者肾小球足细胞病变，分析其与血糖控制、蛋白尿、肾功能及肾组织病理形态学改变之间的关系。方法：27例经肾穿刺活检明确诊断的2型糖尿病肾病。肾组织病理定量计数肾小球足细胞数。借助足细胞特定标志物WTl与肾小球基膜Ⅳ型胶原α3链(C—Ⅳα3)双套色荧光染色，用激光共聚焦荧光显微镜对肾小球足细胞进行准确的密度定量分析。结果：糖尿病肾病患者无论临床表现为微量白蛋白尿、蛋白尿(尿蛋白＜3．5g/24h)，还是大量蛋白尿(尿蛋白＞3．5g/24h)，均伴肾小球足细胞数目及密度的减少，其中以大量蛋白尿组最为显著，蛋白尿组次之，微量白蛋白尿组最轻。足细胞数目及其密度与尿蛋白量呈显著负相关(P＜0．01)。足细胞数目的减少还与肾小球病理改变相关，表现为肾小球K—W结节病变者其足细胞数明显少于肾小球弥漫系膜增生性病变者(P＜0．01)。此外，足细胞数减少严重者肾小球硬化以及血清肌酐水平升高的发生率均明显增高。结论：糖尿病肾病患者早期就表现出肾小球足细胞数目及其密度的减少，随着病变加重，这种变化愈发明显。足细胞病变不仅导致大量蛋白尿的发生，而且还与肾小球硬化和肾功能损伤的发生有关。     

血清胱抑素C在2型糖尿病不同肾损害期的变化及其临床意义

目的探讨血清胱抑素C在2型糖尿病不同肾损害期的变化及其临床意义,比较血清胱抑素C与肾小球滤过率、尿微量白蛋白排泄率间的相关性。方法采用颗粒增强散射免疫比浊法测定102例2型糖尿病患者(其中并糖尿病肾病66例)血清胱抑素水平,同时测定肾小球滤过率和尿微量白蛋白排泄率。结果2型糖尿病正常白蛋白尿组,2型糖尿病微量白蛋白尿组及2型糖尿病大量白蛋白尿组间血清胱抑素C水平均有显著差异(P<0.01),2型糖尿病微量白蛋白尿组和2型糖尿病大量白蛋白尿组血清胱抑素C测值与肾小球滤过率有良好的相关性(P<0.05)。结论血清胱抑素C在临床上可作为肾小球滤过率的判断指标,且有助于2型糖尿病肾病的早期诊断。     

正常白蛋白尿糖尿病患者的临床表现及肾组织损伤

目的:观察正常白蛋白尿糖尿病患者肾组织损伤的特点,以及与尿白蛋白进展、肾小球滤过率(GFR)下降相关的临床和病理风险因素。方法:纳入尿白蛋白定量30 mg/24h,血清肌酐≤109.62μmol/L,并愿意接受肾活检的2型糖尿病患者41例。记录患者基线临床指标和病理指标,并与同期接受肾活检的39例微量白蛋白尿(MAU)早期糖尿病肾病(DN)患者进行比较。尿白蛋白进展定义:随访中连续两次尿白蛋白≥30mg/24h;eGFR下降定义为随访中eGFR下降≥3.3%/年。结果:41例正常白蛋白尿的2型糖尿病患者(NORUAE组)均表现出不同程度的肾小球体积增大、系膜增生及肾小球基膜(GBM)增厚,且与MAU组患者病理改变无统计学差异。肾小球超微结构测量显示NOR-UAE组裂孔膜分布频率显著高于MAU组(1.18±0.39个/μm vs0.83±0.35个/μm,P0.001)。随访中10例患者出现MAU,尿白蛋白进展组肾小球体积显著大于非进展组[(501.04±102.45)×104μm3vs(377.12±82.12)×104μm3,P=0.001],GBM厚度大于非进展组(604.54±194.96 nm vs 478.84±122.60 nm,P=0.041);多因素COX回归分析显示,GBM厚度(P=0.017)和肾小球体积(P=0.017)是尿白蛋白进展的独立风险因素。随访中5例患者出现eGFR下降,其基线eGFR显著低于稳定组和升高组,GBM厚度和足突宽度大于eGFR稳定组,Logistic回归分析显示基线eGFR是eGFR下降的独立风险因素[HR0.774(0.615~0.973),P=0.028]。结论:尿白蛋白正常的2型糖尿病患者已出现DN病理损伤特点,肾小球体积增大和GBM增厚是进展至MAU的独立风险因素;基线eGFR是eGFR下降的独立风险因素。     

足细胞与蛋白尿发病机制的研究进展

蛋白尿是肾脏疾病最常见的表现之一,其发生与肾小球滤过屏障的异常有密切关系。肾小球滤过屏障由毛细血管内皮细胞、肾小球基底膜(GBM)及脏层上皮细胞即足细胞组成。肾小球滤过膜具有电荷屏障和孔径屏障功能,任一屏障损伤均会产生蛋白尿。足细胞位于GBM最外侧,是避免机体蛋白丢     

足细胞损伤与糖尿病肾病

糖尿病肾病(diabetic nephropathy,DN)是糖尿病的主要并发症。1936年Kimmelstiel等[1]第一次描述DN时,系膜基质增多和肾小球基底膜(glomerular basement mem-brane,GBM)增厚就被描述为DN的主要病理表现。研究也证实,系膜增生与蛋白尿、肾功能恶化密切相关。但是,系膜增生并不能解释蛋白尿的发生,因为由肾小球内皮细胞、GBM、足细胞构成的肾小球滤过屏障的损伤才是蛋白尿的根源。事实上,肾小球内皮细胞和GBM参与了DN蛋白尿的发生,但两者均是有孔的,均允许某些蛋白通过[2]。因此,足细胞构成了蛋白滤过的最后一道屏障,但其在DN中的生物…     

住院2型糖尿病患者血清脂蛋白(a)水平及与糖尿病肾病的关系

目的 研究2型糖尿病患者血清脂蛋白(a)水平的变化,探讨其与糖尿病肾病的关系.方法 2007年1月至2008年11月我院内分泌代谢科收治的2型糖尿病患者1238例,年龄15～89岁,记录血压、体质量及病程,入院第2天测定卒腹及餐后2 h血糖、血脂谱、肾功能及尿白蛋白排泄率,应用肾脏病膳食改良试验公式计算肾小球滤过率.分别根据患者年龄、尿白蛋白排泄率及脂蛋白(a)水平进行分层.采用t检验、方差分析、多元逐步回归分析等进行统计学分析.结果 不同年龄组患者血清脂蛋白(a)水平差异无统计学意义(F=1.144,P>0.05).大量蛋白尿组血清脂蛋白(a)水平显著高于正常蛋白尿组和微量蛋白尿组(F=4.113,P<0.05).研究队列按照血清脂蛋白(a)的四分位点分为四组,随着血清脂蛋白(a)水平的升高,尿白蛋白排泄率逐渐升高(F=7.877,P<0.01),而肾小球滤过率逐渐降低(F=4.479,P<0.01).血清脂蛋白(a)与血清总胆固醇、低密度脂蛋白胆固醇、尿白蛋白排泄率呈正相关(r值分别为0.152、0.169、0.18,均P<0.01),与肾小球滤过率呈负相关(r=-0.061,P<0.01).多元逐步同归分析结果显示:影响尿白蛋白排泄率的主要因素包括收缩压、血清脂蛋白(a)水平、低密度脂蛋白胆固醇、肾小球滤过率、年龄.结论 2型糖尿病患者血清脂蛋白(a)水平不受年龄、病程及血糖控制情况的影响,是尿白蛋白排泄率的独立影响因素.     

生化指标对2型糖尿病早期肾病的诊断及其进展风险的价值分析

目的探讨生化指标在2型糖尿病(T2DM)并发糖尿病早期性肾病(DKD)患者中的变化及应用价值。方法依据尿白蛋白与尿肌酐比值(UACR),将2021年1—5月在福建医科大学附属协和医院内分泌科收治的190例2型糖尿病患者分为正常蛋白尿组、微量蛋白尿组和大量蛋白尿组;另选50名健康体检者作为对照组。比较无肾病单纯糖尿病组、微量蛋白尿组和大量蛋白尿组及对照组的各生化指标水平,研究各指标水平与DKD的相关性,并对有统计差异的指标用多元有序Logistic回归分析影响DKD进展的危险因素。结果 C肽、空腹血糖、三酰甘油、尿素、肌酐、光抑素C、肾小球滤过率、尿微量白蛋白、尿α1微球蛋白和糖化血红蛋白水平、UACR与T2DM、DKD相关,差异有统计学意义(P0.05)。尿素、肾小球滤过率和尿微量白蛋白水平对糖尿病肾病的进展存在显著性影响(P0.05)。结论尿素、尿微量白蛋白是糖尿病并发糖尿病肾病及其进展的危险因素,肾小球滤过率为保护因素,这3个指标对DKD有重要的诊断和预测价值。     

老年2型糖尿病患者不同尿白蛋白分期与胰岛素抵抗的关系

目的 研究老年2型糖尿病患者不同尿白蛋白分期与胰岛素抵抗之间的相关性.方法 根据患者24h内的尿微量白蛋白量,把212例2型糖尿病患者分成正常组、微量组和大量组.分别测定三组的空腹血糖、体质指数、空腹胰岛素、血压、血脂、血尿酸、糖化血红蛋白、24h尿白蛋白定量等.最后计算胰岛素抵抗指数及估算肾小球滤过率.结果 微量白蛋白尿组的年龄、血压和胰岛素抵抗指数均高于正常组(P＜0.05),大量白蛋白尿组血压、空腹胰岛素、空腹血糖、胰岛素抵抗指数、血压大于微量组(P＜0.05);肾小球滤过率随着尿白蛋白量增加有明显下降趋势(P＜0.05).结论 老年2型糖尿病患者尿白蛋白的增加与胰岛素抵抗密切相关.     

α3β1整合素与肾小球足细胞脱落的研究进展

肾小球是肾脏滤过单位,其滤过功能与滤过屏障密切相关.肾小球滤过屏障可有效阻止白蛋白等大分子量物质进入尿液,其结构和功能的改变是蛋白尿产生的病理生理基础.肾小球滤过屏障由内而外分为三层:①首先是带窗孔的肾小球内皮细胞;②其次为肾小球基底膜(GBM),这是一高度水化的胶原网,对白蛋白及其他血浆大分子物质兼有分子及电荷屏障作用,GBM含有紧密交联的层黏连蛋白(LN)、Ⅳ型胶原(Ⅳ-collagen)、纤维连接蛋白(FN)和硫酸乙酰肝素蛋白多糖(HSPG),GBM中主要的HSPG是集聚蛋白(agrin),这些HSPG构成GBM的高度阴电荷;③足突(FP)及覆盖于FP裂隙间的裂孔隔膜(SD).足细胞作为肾小球滤过膜的重要组成部分,在维持肾小球正常滤过方面具有至关重要的作用.足细胞从GBM上脱落会导致肾小球滤过屏障的完整性遭到破坏.足细胞通过许多分子锚定于GBM上,如:α3β1整合素、αβ蛋白聚糖复合体(αβdystroglycan complex)、辅肌动蛋白(α-actinin)、组织蛋白酶-L(cathepsin-L)、尿激酶纤维蛋白酶原激活剂受体(UPAR)、磷酸二酯酶抑制剂(B7-1)等[1～5],其中α3β1整合素与足细胞脱落之间的关系最近成为研究热点.本文就α3β1整合素与足细胞脱落的相互关系作一综述.     

Ultrastructural changes in the glomerular filtration barrier and occurrence of proteinuria in Chinese patients with type 2 diabetic nephropathy

AimDiabetic nephropathy (DN) is one of the most important causes of end stage renal disease in the world. Its hallmark is proteinuria. Therefore, we set out to clarify the structural changes that occur in the glomerular filtration barrier in Chinese patients with true type 2 diabetic nephropathy, and to examine the relationship between these structural changes and proteinuria.Methods42 Chinese patients with true T2DN were divided into three groups according to urinary protein excretion. Glomerular volume, endothelial cell density, endothelial cell number, glomerular basement membrane (GBM) width, podocyte density, podocyte number and foot process width were evaluated using light and electron microscopic morphometry.ResultGlomerular volume and endothelial cell number were increased in diabetic patients, but there was no difference between patients with respect to the degree of proteinuria. As proteinuria progressed, endothelial cell density remained unchanged, while the glomerular basement membrane (GBM) and podocyte foot process width increased, podocyte density and number decreased.ConclusionsPodocyte and GBM change more obviously during the development of proteinuria. Besides, proteinuria was inversely related to podocyte density, and directly related to GBM and glomerular volume.     

Causes and consequences of proteinuria: the kidney filtration barrier and progressive renal failure

The past few years have witnessed a major breakthrough in the understanding of the molecular mechanisms and ultrastructural changes behind the development of proteinuria. The discovery of several proteins in the glomerular podocyte and slit diaphragm, where mutations lead to disease, has revealed the importance of this cell with its diaphragm as the major filtration barrier as opposed to the glomerular basement membrane (GBM) previously ascribed this function. Furthermore, accumulating clinical as well as experimental evidence points to the harmful effects of proteinuria, irrespective of the original damage. The purpose of this review is to shed light on what we know today about the two sides of this 'coin', the causes and the consequences of proteinuria.     

Glomerular epithelial foot processes and filtration slits in IDDM patients

Summary Diabetic nephropathy is associated with functional changes in the glomerular filtration barrier but the structural counterpart remains unknown. Width of glomerular epithelial cell foot processes and of filtration slits were determined by morphometric methods in 11 non-diabetic kidney donors and in 28 diabetic patients with albumin excretion rates ranging from normal to proteinuria. Foot process width was estimated from the ratio of tuft surface density to length density of slits. At high magnification independently sampled, perpendicularly cut slits were classified. Foot process width on peripheral basement membrane was increased in microalbuminuric compared to normoalbuminuric diabetic patients (p<0.05) but showed no significant correlation with the level of albumin excretion when patients with increased barrier permeability were considered. Width of filtration slits in normo- and microalbuminuric diabetic patients exceeded that in non-diabetic control subjects (p<0.05). Filtration slits were narrower in patients with overt proteinuria than in patients with microalbuminuria (p<0.05) and correlated with glomerular filtration rate in all of the diabetic patients (r=0.65, p<0.005). The results show that insulin-dependent diabetic patients with nephropathy present changes of epithelial cells and filtration slits, demonstrable already in the stage of microalbuminuria. The mechanism of albumin leakage is not achieved by these measures. The dimension of filtration slits may play a contributing role in the level of glomerular filtration rate in diabetic patients.Abbreviations IDDM Insulin-dependent diabetes mellitus - GFR glomerular filtration rate - AER albumin excretion rate - HbA_1c glycated haemoglobin - ND non-diabetic control subjects - D_NA diabetic patients with normal albumin excretion rate - D_MI diabetic patients with microalbuminuria - D_P diabetic patients with proteinuria - CV coefficient of variation (SD/mean) - FPW_PBM width of foot processes on peripheral basement membrane - FPW_MES width of foot processes on glomerular mesangium - ANOVA analysis of variance - PBM peripheral basement membrane     

Bothrops moojeni snake venom-induced renal glomeruli changes in rat

The venom of Bothrops moojeni has potent proteolytic and phospholipase A2 activities. In previous work, we showed that intravenous injection of this venom in rats decreased creatinine clearance and caused tubular dysfunction and histopathological changes with no alterations in blood pressure. The current study used scanning and transmission electron microscopy to assess the ultrastructural changes caused by B. moojeni venom (0.4 mg/kg i.v.) in rat renal glomeruli and correlated these alterations with the severity of proteinuria 5 hours, 16 hours, and 48 hours after venom injection. The changes included mesangiolysis, glomerular microaneurysms, and glomerular basement membrane (GBM) abnormalities. In addition, there was a reduction in the number and width of podocyte pedicels, which caused a reduction in the number of filtration slits. Electron-dense amorphous material, which may be proteinaceous in origin, was found in the pedicels. The severity of the ultrastructural abnormalities correlated with the level of proteinuria. These morphophysiological changes were attributed to biochemical and physiological disturbances in the components of the GBM and mesangial matrix as well as in cytoskeleton-associated proteins of podocytic processes, and could account for the breakdown of optimal glomerular filtration barrier functioning. These results, together with the absence of appreciable glomerular fibrin deposits, support the hypothesis of a direct activity of B. moojeni venom on rat kidneys. Proteolytic activity of the venom on renal glomeruli could then contribute to the onset of acute renal failure, and would explain the clinical manifestations of renal injury after bites by this and other Bothrops species.     

Pathogenesis of the podocytopathy and proteinuria in diabetic glomerulopathy

Microalbuminuria is the earliest detectable clinical abnormality in diabetic glomerulopathy. On a molecular level, metabolic pathways activated by hyperglycemia, glycated proteins, hemodynamic factors, and oxidative stress are key players in the genesis of diabetic kidney disease. A variety of growth factors and cytokines are then induced through complex signal transduction pathways. Transforming growth factor-beta 1 (TGF-beta1) has emerged as an important downstream mediator for the development of renal hypertrophy and the accumulation of mesangial extracellular matrix components, but there is limited evidence to support its role in the development of albuminuria. The loss of proteoglycans in the glomerular basement membrane (GBM) has been recently questioned as causative of the albuminuria, and current research has focused on the podocyte as a central target for the effects of the metabolic milieu in the development and progression of diabetic albuminuria. Podocyte-derived vascular endothelial growth factor (VEGF), a permeability and angiogenic factor whose expression is increased in diabetic kidney disease, is perhaps a major mediator of the increased protein filtration. Decreased podocyte number and/or density as a result of apoptosis or detachment, GBM thickening with altered matrix composition, and a reduction in nephrin protein in the slit diaphragm with podocyte foot process effacement, all comprise the principal features of diabetic podocytopathy that clinically manifests as albuminuria and proteinuria. Many of these events are mediated by angiotensin II whose local concentration is stimulated by high glucose, mechanical stretch, and proteinuria itself. Angiotensin II in turn stimulates podocyte-derived VEGF, suppresses nephrin expression, and induces TGF-beta1 leading to podocyte apoptosis and fostering the development of glomerulosclerosis. Proteinuria can then induce in tubular cells a genetic program leading to tubulointerstitial inflammation, fibrosis and tubular atrophy. Besides direct effects of albuminuria on tubular cells, pathophysiological changes in the ultrafiltration barrier lead to an increased tubular filtration of various growth factors (TGF-beta1, insulin-like growth factor I) that may further alter the function of tubular cells. Moreover, angiotensin II also stimulates uptake of ultrafiltered proteins into tubular cells and enhances the production of proinflammatory and profibrotic cytokines within the cells. Migration of macrophages and other inflammatory cells into the tubulointerstitium occurs. Increased synthesis and decreased turnover of extracellular matrix proteins in tubular cells and interstitial fibroblasts contribute to interstitial fibrosis. In addition, under locally high concentrations of angiotensin II and TGF-beta1, tubular cells may change their phenotype and become fibroblasts by a process called epithelial to mesenchymal transition (EMT) which contributes to interstitial fibrosis and tubular atrophy because of vanishing epithelia cells. An alternative explanation for the development of albuminuria in diabetic nephropathy that involves primarily an abnormality in tubular handling of ultrafiltered proteins has also been suggested, but these changes are not necessarily exclusive of the altered properties of glomerular ultrafiltration barrier.     

Selective proteinuria in diabetic nephropathy in the rat is associated with a relative decrease in glomerular basement membrane heparan sulphate

Summary In the present study we investigated whether glomerular hyperfiltration and albuminuria in streptozotocin-induced diabetic nephropathy in male Wistar-Münich rats are associated with changes in the heparan sulphate content of the glomerular basement membrane. Rats with a diabetes mellitus duration of 8 months, treated with low doses of insulin, showed a significant increase in glomerular filtration rate (p<0.01) and effective renal plasma flow (p<0.05), without alterations in filtration fraction or mean arterial blood pressure. Diabetic rats developed progressive albuminuria (at 7 months, diabetic rats (D): 42±13 vs control rats (C): 0.5±0.2 mg/ 24 h, p<0.002) and a decrease of the selectivity index (clearance IgG/clearance albumin) of the proteinuria (at 7 months, D: 0.20±0.04 vs C: 0.39±0.17, p<0.05), suggesting loss of glomerular basement membrane charge. Light- and electron microscopy demonstrated a moderate increase of mesangial matrix and thickening of the glomerular basement membrane in the diabetic rats. Immunohistochemically an increase of laminin, collagen III and IV staining was observed in the mesangium and in the glomerular basement membrane, without alterations in glomerular basement membrane staining of heparan sulphate proteoglycan core protein or heparan sulphate. Giomerular basement membrane heparan sulphate content, quantitated in individual glomerular extracts by a new inhibition ELISA using a specific anti-glomerular basement membrane heparan sulphate monoclonal antibody (JM403), was not altered (median (range) D: 314 (152–941) vs C: 262 (244–467) ng heparan sulphate/mg glomerulus). However, the amount of glomerular 4-hydroxyproline, as a measure for collagen content, was significantly increased (D: 1665 (712–2014) vs C: 672 (515–1208) ng/mg glomerulus, p<0.01). Consequently, a significant decrease of the heparan sulphate/4-hydroxyproline ratio (D: 0.21 (0.14–1.16) vs C: 0.39 (0.30–0.47), p<0.05) was found. In summary, we demonstrate that in streptozotocin-diabetic rats glomerular hyperfiltration and a progressive, selective proteinuria are associated with a relative decrease of glomerular basement membrane heparan sulphate. Functionally, a diminished heparan sulphate-associated charge density within the glomerular basement membrane might explain the selective proteinuria in the diabetic rats.Abbreviations BW Body weight - ERPF effective renal plasma flow - GAG glycosaminoglycan - GBM glomerular basement membrane - GFR glomerular filtration rate - HS heparan sulphate - HSPG heparan sulphate proteoglycan - IDDM insulin-dependent diabetes mellitus - STZ streptozotocin     

Prevention and treatment of diabetic nephropathy

Increasing number of diabetic patients develop different stages of renal failure. However, often an inappropriate parameter, the serum creatinine is measured as a marker of glomerular function. Calculated glomerular filtration rate or endogenous creatinine clearance are suggested to be used for the estimation of the glomerular function. Important structures preventing proteinuria in the kidney are glomerular basement membrane, podocytes and proximal tubular cells. In diabetes mellitus loss of nephrin of podocytes can play a role in the development of microalbuminuria, and podocyte desquamation may result in the progression to proteinuria. In diabetes mellitus there is an increased formation of advanced glycation endproducts (AGE), of which the only elimination organ is the kidney. The AGE induce proteinuria and atherosclerosis. Therefore, in diabetes mellitus a vicious circle develops due to proteinuria, nephron loss and accumulation of AGE, which play a role in the initiation and progression of diabetic nephropathy and atherosclerosis. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers having antiproteinuric effect may decrease the risk of diabetic nephropathy and atherosclerosis. Improvement of carbohydrate metabolism with a consequential decrease in the formation of AGE is an important contributor to the prevention and treatment of diabetic nephropathy and atherosclerosis.     

糖尿病糖脂代谢紊乱与足细胞损害的实验研究

目的　观察糖脂代谢紊乱对糖尿病大鼠肾小球滤过屏障外层足细胞的影响 ,以探讨糖尿病肾病的发病机制。方法　采用链脲佐菌素诱导糖尿病大鼠模型 ,喂养 5周后 ,测定血糖、糖化血红蛋白、甘油三酯、总胆固醇、血肌酐、尿素氮和尿白蛋白排泄率 ,应用免疫组化检测肾小球足细胞损伤标志蛋白 -desmin的表达 ,同时利用透射电子显微镜观察肾小球足细胞超微结构。结果　糖尿病大鼠血糖、糖化血红蛋白、总胆固醇、血肌酐、尿素氮、尿白蛋白排泄率水平明显升高 (P <0 .0 5 ) ,肾小球内desmin蛋白表达上调 ,足细胞部分足突融合 ;同时 ,两组间血甘油三酯水平无显著性差异 (P >0 .0 5 )。结论　糖脂代谢紊乱可导致糖尿病大鼠肾小球滤过屏障外层足细胞明显损害 ,尿白蛋白排泄率增加 ,这可能是糖尿病肾脏损害、蛋白尿出现的机制之一     

The glomerular podocyte as a target of growth hormone action: implications for the pathogenesis of diabetic nephropathy

Involvement of the growth hormone (GH) / insulin-like growth factor 1 (IGF-I) axis in the pathogenesis of diabetic nephropathy (DN) is strongly suggested by studies investigating the impact of GH excess and deficiency on renal structure and function. GH excess in both the human (acromegaly) and in transgenic animal models is characterized by significant structural and functional changes in the kidney. In the human a direct relationship has been noted between the activity of the GH/IGF-1 axis and renal hypertrophy, microalbuminuria, and glomerulosclerosis. Conversely, states of GH deficiency or deficiency or inhibition of GH receptor (GHR) activity confer a protective effect against DN. The glomerular podocyte plays a central and critical role in the structural and functional integrity of the glomerular filtration barrier and maintenance of normal renal function. Recent studies have revealed that the glomerular podocyte is a target of GH action and that GH's actions on the podocyte could be detrimental to the structure and function of the podocyte. These results provide a novel mechanism for GH's role in the pathogenesis of DN and offer the possibility of targeting the GH/IGF-1 axis for the prevention and treatment of DN.