细胞焦亡与糖尿病肾病肾间质纤维化

肾间质纤维化是糖尿病肾病等慢性肾脏疾病进展至终末期肾病的不可逆性危险因素。细胞焦亡是一种新型程序性细胞死亡,通过诱导炎症反应的发生参与糖尿病肾病。焦亡引起的慢性炎症和纤维化被认为是糖尿病肾病发病的重要因素。因此,明确细胞焦亡与糖尿病肾病肾间质纤维化之间的关系对延缓糖尿病肾病进展至关重要。本文综述了近年来细胞焦亡在糖尿病肾病肾间质纤维化发病机制中的研究进展,以期为临床防治糖尿病肾病提供更多的理论基础。     

硫化氢在肾脏病中的保护作用

肾脏病发病率逐年增高,已经成为影响人类健康的重要疾病之一。硫化氢是继NO、CO之后的第三种气体信号分子,大剂量有毒害作用,但生理浓度的硫化氢起到舒张血管、抗氧化、抗炎、抗凋亡等重要作用。肾脏病尤其继发性肾脏病如梗阻性肾病、肾移植、糖尿病肾病及高血压性肾损害等与血管病变、氧化应激、炎症密切相关,那么硫化氢与肾脏疾病之间有怎样的关系,本文将就硫化氢在肾脏病中的保护作用做一综述。     

法尼酯衍生物X受体（FXR）在糖尿病肾病中的研究进展

糖尿病肾病（DN）是糖尿病常见的慢性微血管并发症,最初是由高血糖引起的肾脏适应性高滤过率,进而导致肾脏细胞的代偿性增生、炎症以及纤维化。法尼酯X受体（FXR）被证明对糖尿病肾病有负性调节的作用,FXR可以通过不同的方面（血糖、血脂、炎症以及纤维化）对糖尿病肾病进行调控,从而有效的控制糖尿病肾病的发生和发展。本文将对FXR以及FXR调控糖尿病肾病的不同方面予以综述。     

mTOR信号通路在糖尿病肾病发病机制中作用的研究进展

糖尿病肾病是目前终末期肾脏疾病的主要原因,给患者家庭及社会带来沉重负担,如何预防及治疗糖尿病肾病成为亟需解决的问题。然而,糖尿病肾病的发病机制极其复杂,其中mTOR信号通路在其中扮演着重要角色。该综述主要总结了mTOR信号通路对糖尿病肾病的影响并阐述其可能存在的机制,希望能够给予同行些许借鉴。     

多囊肾病动物模型的研究进展

多囊肾病(Polycystic kidney disease,PKD)是以肾脏充满多个液性囊泡,细胞增殖异常,间质炎细胞浸润及细胞外基质重塑等病理特点为主的遗传性疾病。主要分为常染色体显性多囊肾病(Autosomal dominant polycystic kidney disease,ADPKD)及常染色体隐性多囊肾病(Autosomal recessive polycystic kidney disease,ARPKD)。ADPKD更为常见,发病率约为1:500-1000,约50%的患者到60岁会发展为终末期肾脏病。ARPKD较少见,发病率约为1:20000-1:40000,患者多在婴幼儿时期死亡。目前,一旦多囊肾发展为终末期肾脏病,除了肾脏移植和透析外没有更有效的治疗方法,因此,早期的诊治对延缓多囊肾进展及防止其发展为终末期肾脏病是至关重要的。多囊肾动物模型的建立在研究多囊肾疾病具体发病机制及新药研发中具有重要意义。本文介绍了PKD疾病动物模型的研究进展,包括经典PKD自发模型、化学诱导模型及基因修饰模型。     

NF-kB 信号通路与糖尿病肾病治疗研究进展

糖尿病肾病是由于糖尿病糖代谢异常为主因所致的肾小球硬化并伴尿蛋白含量超过正常的疾病,它是糖尿病引起的严重 和危害性最大的一种慢性并发症。对糖尿病肾病的防御与治疗仍是临床研究的热点之一。NF-kB 信号通路是一条由核因子 NF-kB 及其受体、免疫调节蛋白等组成的高度保守的信号通路,参与免疫反应、炎症反应、细胞凋亡、肿瘤发生等多种生物学进 程。作为参与糖尿病肾病的主要信号通路之一,激活NF-kB 信号通路能进一步扩大糖尿病肾病的炎症反应。因此本文就NF-资B 激活与DN 炎症反应的关系以及NF-资B的抗炎策略做一综述,为糖尿病肾病的预防和治疗提供科学数据和理论依据。     

NF-κB信号通路与糖尿病肾病治疗研究进展

糖尿病肾病是由于糖尿病糖代谢异常为主因所致的肾小球硬化并伴尿蛋白含量超过正常的疾病,它是糖尿病引起的严重和危害性最大的一种慢性并发症。对糖尿病肾病的防御与治疗仍是临床研究的热点之一。NF-κB信号通路是一条由核因子NF-κB及其受体、免疫调节蛋白等组成的高度保守的信号通路,参与免疫反应、炎症反应、细胞凋亡、肿瘤发生等多种生物学进程。作为参与糖尿病肾病的主要信号通路之一,激活NF-κB信号通路能进一步扩大糖尿病肾病的炎症反应。因此本文就NF-κB激活与DN炎症反应的关系以及NF-κB的抗炎策略做一综述,为糖尿病肾病的预防和治疗提供科学数据和理论依据。     

糖尿病肾病致凝血异常的研究

糖尿病(DM)已成为世界性的常见病,其发病率高,并且随着生活水平的改善,其发病率必然还会进一步加剧。血管病变是DM的重要并发症之一,糖尿病肾病(DN)是糖尿病常见且严重的微血管并发症,与血栓形成密切相关。糖尿病肾病的进展伴随着体内凝血活性和抗凝活性的失调,同时激活自身免疫系统,发生炎症反应。炎症应答过程中释放的炎症因子损伤肾小球内皮细胞,导致抗凝活性减弱。DN患者体内血细胞激活,微粒形成增多会加强凝血活性。此外,纤溶酶抑制剂(PAI-1)与纤溶酶激活剂(t PA)的失衡会引起纤溶系统紊乱。这三个方面引起DN患者体内的高凝状态加重,并因此加速肾功能恶化,导致肾小球率过滤降低,系膜基质增多,最终引起肾小球硬化及终末期肾脏疾病。本文就糖尿病肾病致凝血异常的发生机制做一综述。     

甘草甜素抗炎及抗肿瘤机制研究进展

甘草甜素是中药甘草的主要成分,具有抗炎、抗病毒、抗肿瘤等作用,随着研究的不断深入,甘草甜素广泛地应用于银屑病、慢性肝病、艾滋病及肿瘤等疾病的治疗中。近年来,学者对其抗炎和抗肿瘤作用研究较为突出,其机制包括抑制炎症因子、抗氧化、免疫调节、抗血管生成等,为更好地指导临床应用,就目前甘草甜素抗炎和抗肿瘤机制作一综述。     

1-磷酸鞘氨醇在肾脏纤维化中的作用及其调控

肾脏纤维化是原发或继发性肾脏病持续进展至终末期肾病的共同病理过程。1-磷酸鞘氨醇是一种具有生物活性的神经鞘脂类代谢物,参与组织纤维化的发生。研究发现,1-磷酸鞘氨醇在成纤维细胞转分化为肌成纤维细胞过程以及纤维化早期阶段炎症反应的诱导中发挥着关键作用。本文主要介绍1-磷酸鞘氨醇在肾脏纤维化中的作用及其调控,旨在更进一步认识肾脏纤维化发病机制,为肾脏纤维化疾病的预防及治疗提供新的靶向。     

Genipin inhibits mitochondrial uncoupling protein 2 expression and ameliorates podocyte injury in diabetic mice

Diabetic nephropathy (DN) is one of the most common causes of end stage renal disease (ESRD) in China, which requires renal replacement therapy. Recent investigations have suggested an essential role of podocyte injury in the initial stage of DN. This study investigated the potential therapeutic role of genipin, an active extract from a traditional Chinese medicine, on progression of DN in diabetic mice induced by intraperitoneally injection of streptozocin (STZ). In diabetic mice, orally administration of genipin postponed the progression of DN, as demonstrated by ameliorating body weight loss and urine albumin leakage, attenuating glomerular basement membrane thickness, restoring the podocyte expression of podocin and WT1 in diabetic mice. The protective role of genipin on DN is probably through suppressing the up-regulation of mitochondrial uncoupling protein 2 (UCP2) in diabetic kidneys. Meanwhile, through inhibiting the up-regulation of UCP2, genipin restores podocin and WT1 expression in cultured podocytes and attenuates glucose-induced albumin leakage through podocytes monolayer. Therefore, these results revealed that genipin inhibited UCP2 expression and ameliorated podocyte injury in DN mice.     

糖尿病肾病动物模型的研究进展

糖尿病肾病是终末期肾衰的主要原因,也是糖尿病致命的重要原因。但是糖尿病肾病的致病机制迄今尚不完全明了,理想的动物模型无疑可对糖尿病肾病的研究提供重要线索。糖尿病肾病动物模型包括诱发性、自发性和转基因等多种类型的动物模型,各种类型的动物模型在疾病的发生发展、病理生理变化等多个方面与人类糖尿病肾病具有相似的特征。应用这些模型有助于开展对糖尿病肾病的防治、发病机理、相关药物的开发等多方面的研究。     

糖尿病肾病发病机制研究进展

糖尿病肾病(DN)是糖尿病(DM)最常见的慢性并发症,也是终末期肾病(ESRD)的主要原因,其治疗费用巨大。其发病机制主要涉及遗传易感性、糖代谢紊乱、肾血流动力学的改变、细胞因子、炎症机制已及氧化应激等方面。本文就以上作用机制的最新研究进展作一综述。     

具有抗炎活性的中药对脂肪酸合酶的抑制作用

随着肥胖及其相关疾病的患病率不断上升,肥胖并发的慢性炎症已成为一个不容忽视的公共卫生问题,迫切需要针对肥胖相关慢性炎症新的治疗方案和干预策略。脂肪酸合酶(Fatty acid synthase,FAS)是一种多功能复合酶,是治疗肥胖、糖尿病、非酒精性脂肪肝、炎症和癌症的潜在靶点。持续的炎症反应是潜在的危险因素。一些关键的炎症标志物与肥胖密切相关,其中特别是FAS抑制剂的研究受到越来越多的关注。在我国,中药已广泛被应用于炎症的治疗,其中有多种中药对FAS表现出强抑制作用。本文综述了中药FAS抑制剂的结构和活性特点,对于研发中药FAS抑制剂治疗炎症提供了依据。     

The mTOR pathway is highly activated in diabetic nephropathy and rapamycin has a strong therapeutic potential

Diabetic nephropathy (DN) associated with type 2 diabetes is the most common cause of end-stage renal disease (ESRD) and a serious health issue in the world. Currently, molecular basis for DN has not been established and only limited clinical treatments are effective in abating the progression to ESRD associated with DN. Here we found that diabetic db/db mice which lack the leptin receptor signaling can be used as a model of ESRD associated with DN. We demonstrated that p70S6-kinase was highly activated in mesangial cells in diabetic obese db/db mice. Furthermore, systemic administration of rapamycin, a specific and potent inhibitor of mTOR, markedly ameliorated pathological changes and renal dysfunctions. Moreover, rapamycin treatment shows a significant reduction in fat deposits and attenuates hyperinsulinemia with few side effects. These results indicate that mTOR activation plays a pivotal role in the development of ESRD and that rapamycin could be an effective therapeutic agent for DN.     

miR-218 regulates diabetic nephropathy via targeting IKK-β and modulating NK-κB-mediated inflammation

Diabetic nephropathy (DN) is a common clinically relevant complication of diabetes that is associated with damage to the capillaries, yet the etiology of this condition remains unclear. Nuclear factor-kappa B (NF-κB) activation is known to be associated with DN-related inflammation and disease progression. Recent work indicated that microRNAs are diagnostic biomarkers of DN progression associated with inflammation in the progression of DN. miR-218 is known to play key regulatory roles in certain cancers in humans, while its influence on DN pathology remains uncertain. The present study, therefore, sought to assess how miR-218 influences the progression of disease in both a rat streptozotocin-induced model of DN and as well as an in vitro model system in which mouse podocytes were stimulated with high glucose levels. We found miR-218 to be markedly downregulated in both model systems relative to appropriate controls, and this downregulation was associated with IKK-β upregulation. In DN rat model, overexpressing miR-218 was sufficient to reduce renal injury. We further determined that podocyte proliferation was markedly impaired by glucose treatment, leading to the apoptotic death of these cells, and miR-218 mimics were able to reduce these phenotypes. Overexpressing miR-218 also significantly dampened inflammatory responses in this model system, as evidenced by reduced tumor necrosis factor-α, interleukin-6 (IL-6), IL-1β, and MCP-1 levels. We then confirmed that miR-218 targeting the messenger RNA encoding IKK-β using a dual-luciferase reporter assay. Together, our results provide clear evidence that miR-218 regulate NF-κB-mediated inflammation, which is central to DN progression.     

Schisandrin B alleviates diabetic nephropathy through suppressing excessive inflammation and oxidative stress

Diabetic nephropathy (DN) is a progressive kidney disease due to glomerular capillary damage in diabetic patients, with inflammation and oxidative stress implicated as crucial pathogenic factors. There is an urgent need to develop effective therapeutic drug. Natural medicines are rich resources for active lead compounds. They would provide new opportunities for the treatment of DN. The present study was designed to investigate the protective effects of Schisandrin B (SchB) on DN and to delineate the underlying mechanism. Oral administration of SchB in the diabetic mouse model significantly alleviated hyperglycemia-induced renal injury, which was accompanied by maintenance of urine creatinine and albumin levels at similar to those of control non-diabetic mice. Histological examination of renal tissue indicated that both development of fibrosis and renal cell apoptosis were dramatically inhibited by SchB. The protective effect of SchB on DN associated with suppression of inflammatory response and oxidative stress. These results strongly suggested that SchB could be a potential therapeutic agent for treatment of DN. Moreover, our findings provided a fuller understanding of the regulatory role of NF-κB and Nrf2 in DN, indicating that they could be important therapeutic targets.     

Increased Risk of Urinary Tract Cancer in ESRD Patients Associated with Usage of Chinese Herbal Products Suspected of Containing Aristolochic Acid

Introduction

Both end-stage renal disease (ESRD) and urothelial cancer (UC) are associated with the consumption of Chinese herbal products containing aristolochic acid (AA) by the general population. The objective of this study was to determine the risk of UC associated with AA-related Chinese herbal products among ESRD patients.

Methods

We conducted a cohort study using the National Health Insurance reimbursement database to enroll all ESRD patients in Taiwan from 1998–2002. Cox regression models were constructed and hazard ratios and confidence intervals were estimated after controlling for potential confounders, including age, sex, residence in region with endemic black foot disease, urinary tract infection, and use of non-steroidal anti-inflammatory drugs and acetaminophen.

Results

A total of 38,995 ESRD patients were included in the final analysis, and 320 patients developed UC after ESRD. Having been prescribed Mu Tong that was adulterated with Guan Mu Tong (Aristolochia manshuriensis) before 2004, or an estimated consumption of more than 1–100 mg of aristolochic acid, were both associated with an increased risk of UC in the multivariable analyses. Analgesic consumption of more than 150 pills was also associated with an increased risk of UC, although there was little correlation between the two risk factors.

Conclusion

Consumption of aristolochic acid-related Chinese herbal products was associated with an increased risk of developing UC in ESRD patients. Regular follow-up screening for UC in ESRD patients who have consumed Chinese herbal products is thus necessary.