抗肾间质纤维化药物新进展

肾间质纤维化(RIF)是指由多种细胞、血管活性物质、细胞因子共同参与和相互作用,最终导致细胞外基质(ECM)的过度沉积和成纤维细胞增生,是所有慢性肾脏疾病(CKD)进展至终末期肾脏病(ESRD)的共同病理特征[1].诸多因素参与了肾间质纤维化的病程,包括细胞外基质细胞的增殖和活化,血管活性物质和细胞因子的作用,以及细胞外基质的转换失衡等,有效抑制细胞外基质过度积聚、减少炎症细胞浸润和炎症因子分泌,可延缓CKD进展.本文就近年来抗RIF药物作一综述.     

肾小管周围毛细血管内皮细胞与肾间质纤维化的研究进展

肾间质纤维化是各种慢性肾脏疾病进展到终末期肾病的共同途径和主要病理基础,以往针对肾间质纤维化的研究大多集中于一些细胞外基质的代谢失衡、肾小管上皮细胞凋亡、炎症、氧化应激、细胞因子紊乱等方面。而近几年,随着对肾小管周围毛细血管内皮细胞的不断深入研究,发现其分泌的生物活性物质：一氧化氮、内皮素、血管紧张素Ⅱ等在肾间质纤维化的发生发展中起着重要的作用,并通过不同途径诱导肾间质纤维化的发生与发展。     

肾后性梗阻致肾纤维化机制研究进展

肾纤维化是指各种原因引起正常肾组织结构破坏,被纤维组织取代的病理过程,主要表现为细胞外基质沉积,可引起肾功能减退或肾功能衰竭。急、慢性肾后性梗阻是肾功能损伤及肾纤维化的常见病因。肾后性梗阻致肾纤维化是多种因素共同作用的结果,可能涉及肾组织缺氧微环境,炎症介质释放及炎症细胞浸润,肾间质细胞活化及促纤维化因子释放等。本文就肾后性梗阻致肾纤维化机制的研究进展作一综述。     

肾脏纤维化的发病机制及治疗进展

<正>肾脏纤维化是引发终末期肾功能衰竭的主要原因之一,所有慢性肾脏疾病最终可发展为肾脏纤维化。各种原发性肾小球疾病、输尿管阻塞、糖尿病等均可引发肾间质炎性细胞浸润、肾小管上皮细胞凋亡及肌成纤维细胞聚集,并通过促纤维化因子增加细胞外基质(ECM)的生成,减少其降解,从而形成肾间质纤维化,损伤肾功能[1]。目前,临床上主要通过控制加剧肾功能恶化的危险因素来防治肾脏纤维化,但患者预后改善并不显著[2]。因此,     

细胞外基质与肾纤维化

肾纤维化是肾脏对慢性损伤的病理修复反应，是多种慢性肾病的共同病理基础与慢性肾病向终末期肾衰竭进展的重要过程。肾纤维化发生在肾间质和肾小球等部位，分别表现为肾间质纤维化与肾小球硬化，主要特征为肾小球内系膜细胞增生，细胞外基质（ECM）显著增宽；肾小管和间质毛细血管的丧失及细胞外基质的过度积聚。     

威草胶囊对尿酸性肾病大鼠TGF-β1和TIMP-1G表达的影响

目的 :探讨威草胶囊对尿酸性肾病大鼠的作用机制。方法 :用腺嘌呤加沙丁鱼造模 ,并将大鼠分为正常对照组、模型空白组、小剂量威草胶囊治疗组、大剂量威草胶囊治疗组、别嘌呤醇治疗组。在造模的同时 ,分别给予以上述药物灌胃 ,在实验第 4周 ,活杀所有大鼠 ,取肾组织 ,做肾脏病理组织检查 ,用点计数法计算肾小管的萎缩率 ,炎症细胞浸润面积 ,间质纤维化率 ;应用免疫组织化学技术检测大鼠肾组织TGF β1和TIMP 1(组织基质金属蛋白酶抑制物 -1)的表达情况。结果 :与正常组相比 ,模型空白组和各治疗组TGF β1、TIMP 1阳性表达增高 (P <0 0 1) ;与模型空白组相比 ,治疗组肾小管的萎缩率、炎症细胞浸润面积、间质纤维化率明显减轻 (P <0 0 1) ;TGF β1、TIMP 1阳性表达下降 (P <0 0 1)。结论 :威草胶囊可能通过抑制TGF β1表达 ,抑制细胞外基质和细胞因子的表达分泌 ;通过抑制TIMP 1的表达 ,促进细胞外基质的降解 ,从而减少尿酸性肾病肾间质纤维化。     

ACE2基因——肾脏纤维化干预新靶点

近年来,肾脏纤维化已成为肾脏病学界的研究热点之一。肾脏纤维化是慢性肾脏病(CKD)共同的病理形态学特征,是指在各种致病因子如炎症、各种损伤、高血压、糖尿病等的作用下,肾脏组织出现肾小管萎缩、大量炎症细胞浸润、肾间质成纤维细     

氟伐他汀对单侧输尿管梗阻大鼠肾间质纤维化的影响

[目的]观察氟伐他汀对单侧输尿管梗阻后大鼠肾间质单核细胞趋化蛋白-1(MCP-1)表达、单核/巨噬细胞浸润及肾间质纤维化程度的影响,探讨他汀类药物的抗炎作用机制及对肾脏的保护作用.[方法]72只SD雌性大鼠随机分成假手术(SOR)组、单侧输尿管梗阻术(UUO)组和单侧输尿管梗阻术(UUO) 氟伐他汀治疗组[T-UUO组, 氟伐他汀20 mg/(kg·d)].于术后d3、d7、d10、d14分别处死各组大鼠.用HE及Masson 染色动态观察肾脏病理变化,免疫组织化学法测定MCP-1 的表达和巨噬细胞浸润情况.[结果]UUO组肾小管-间质MCP-1与单核巨噬细胞抗原ED-1表达较SOR组增加(P＜0.05); 在术后各时间点,T-UUO组大鼠肾小管-间质MCP-1、ED-1的表达及肾间质胶原相对面积较UUO模型组显著减少,但仍高于SOR组(P＜0.05).[结论]氟伐他汀可通过降低MCP-1表达、抑制单核-巨噬细胞浸润,减轻肾间质纤维化而对肾脏有保护作用.     

三七总皂苷在肾间质纤维化中的药理作用

目的:总结三七总皂苷对肾间质纤维化的药理学作用,探讨三七总皂苷在防治肾间质纤维化应关注的重要环节及其病理生理机制。资料来源:应用计算机检索Medline1990-01/2006-03关于三七总皂苷在肾间质纤维化中药理作用的文章,检索词“Panaxnotoginoside(PNS),tubu1ointerstitia1fibrosis(TIF),pharmacologicaction”并限定文章的语言种类为“English”。同时利用计算机检索中国期刊全文数据库1990-01/2006-03的相关文章,限定文章语言种类为中文,检索词“三七总皂苷,肾间质纤维化,药理作用”。资料选择:对资料进行初审,选择与三七总皂苷治疗肾间质纤维化的药理作用相关文章52篇,无论研究对象是人还是动物均纳入,排除综述类文献。资料提炼:对选择的文献进一步查找全文,排除不同程度重复的文章,选择近期发表在较权威杂志的18篇文章进行综述。资料综合:肾间质纤维化形成的机制主要是炎症细胞浸润,肾脏固有细胞在致纤维化性生长因子、各种细胞因子等作用下肾小管、肾间质细胞损伤和活化及细胞外基质成分的产生与降解过程的失调而致其过度积聚。临床和科研研究证实三七总皂苷可从细胞水平、分子水平及基因水平防治肾间质纤维化的形成。结论:三七总皂苷防治肾间质纤维化可能与减少胶原及转化生长因子β的表达、抑制肾小管上皮细胞转分化、抑制人肾间质成纤维细胞增殖及促进其凋亡等有关。     

肝细胞生长因子及其受体c-met与肾脏纤维化的动物模型研究

肾纤维化是指在各种致病因素作用下,间质细胞及细胞间质增多,尤其是基质蛋白合成增加、基质降解减少造成细胞外基质(ECM)的大量堆积导致的肾小球硬化和肾小管间质纤维化.这是大部分慢性肾脏病最终的共同表现,常常引起广泛的肾组织瘢痕,并进一步导致肾实质的完全破坏和终末期肾衰竭[1].     

Statins and progressive renal disease.

Thanks to the administration of hypocholesterolemic drugs, important advances have been made in the treatment of patients with progressive renal disease. In vitro and in vivo findings demonstrate that statins, the inhibitors of HMG-CoA reductase, can provide protection against kidney diseases characterized by inflammation and/or enhanced proliferation of epithelial cells occurring in rapidly progressive glomerulonephritis, or by increased proliferation of mesangial cells occurring in IgA nephropathy. Many of the beneficial effects obtained occur independent of reduced cholesterol levels because statins can directly inhibit the proliferation of different cell types (e.g., mesangial, renal tubular, and vascular smooth muscle cells), and can also modulate the inflammatory response, thus inhibiting macrophage recruitment and activation, as well as fibrosis. The mechanisms underlying the action of statins are not yet well understood, although recent data in the literature indicate that they can directly affect the proliferation/apoptosis balance, the down-regulation of inflammatory chemokines, and the cytogenic messages mediated by the GTPases Ras superfamily. Therefore, as well as reducing serum lipids, statins and other lipid-lowering agents may directly influence intracellular signaling pathways involved in the prenylation of low molecular weight proteins that play a crucial role in cell signal transduction and cell activation. Statins appear to have important potential in the treatment of progressive renal disease, although further studies are required to confirm this in humans.     

Statins in heart failure—With preserved and reduced ejection fraction. An update

HMG-CoA reductase inhibitors or statins beyond their lipid lowering properties and mevalonate inhibition exert also their actions through a multiplicity of mechanisms. In heart failure (HF) the inhibition of isoprenoid intermediates and small GTPases, which control cellular function such as cell shape, secretion and proliferation, is of clinical significance. Statins share also the peroxisome proliferator-activated receptor pathway and inactivate extracellular-signal-regulated kinase phosphorylation suppressing inflammatory cascade. By down-regulating Rho/Rho kinase signaling pathways, statins increase the stability of eNOS mRNA and induce activation of eNOS through phosphatidylinositol 3-kinase/Akt/eNOS pathway restoring endothelial function. Statins change also myocardial action potential plateau by modulation of Kv1.5 and Kv4.3 channel activity and inhibit sympathetic nerve activity suppressing arrhythmogenesis. Less documented evidence proposes also that statins have anti-hypertrophic effects – through p21ras/mitogen activated protein kinase pathway – which modulate synthesis of matrix metalloproteinases and procollagen 1 expression affecting interstitial fibrosis and diastolic dysfunction. Clinical studies have partly confirmed the experimental findings and despite current guidelines new evidence supports the notion that statins can be beneficial in some cases of HF. In subjects with diastolic HF, moderately impaired systolic function, low b-type natriuretic peptide levels, exacerbated inflammatory response and mild interstitial fibrosis evidence supports that statins can favorably affect the outcome. Under the lights of this evidence in this review article we discuss the current knowledge on the mechanisms of statins' actions and we link current experimental and clinical data to further understand the possible impact of statins' treatment on HF syndrome.     

Renal tubulointerstitial fibrosis. New thoughts on its development and progression

Current investigation of the pathogenesis of tubulointerstitial injury indicates that both interstitial fibroblasts and renal tubular epithelial cells promote extracellular matrix accumulation. Moreover, two peptides--TGF-beta and angiotensin II--produced locally or delivered in the circulation, appear to play a central role in renal fibrosis. Pharmacologic amelioration of renal fibrosis may require methods directed at multiple factors involved in the fibrotic process, including angiotensin II, TGF-beta, and the proliferation and activation of interstitial fibroblasts.     

Rhabdomyolysis and HMG-CoA reductase inhibitors

OBJECTIVE: To review rhabdomyolysis and discuss the role of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) and their interactions with other agents in precipitating this condition, and to present case reports of statin-induced rhabdomyolysis. DATA SOURCE: Relevant clinical literature was accessed using MEDLINE (January 1985-October 2000). The following search terms were used: rhabdomyolysis, adverse events, drug interactions, statins, and HMG-CoA reductase inhibitors. DISCUSSION: Rhabdomyolysis occurs when extensive muscle damage results in the release of cellular contents into systemic circulation. Major complications include acute renal failure, cardiac abnormalities, and compartment syndrome. Treatment of rhabdomyolysis is supportive, with the primary aim of preventing renal and cardiac complications. Statin monotherapy or combination therapy may result in myopathy, which rarely progresses to rhabdomyolysis. The mechanism for drug interactions with the statins involves their property of lipid or water solubility. This characteristic determines the degree of hepatoenteric or renal metabolism of the statins. All statins except pravastatin undergo metabolism via the cytochrome P450 enzyme system. Other pharmacologic agents that are also metabolized via this pathway may interact with the statins and cause rhabdomyolysis. The risk of statin-induced rhabdomyolysis is increased significantly when statins are used concomitantly with such drugs as fibrates, cyclosporine, macrolide antibiotics, and azole antifungals. CONCLUSIONS: Rhabdomyolysis is a rare but clinically important adverse event of statin monotherapy or combination therapy. Thorough understanding of this condition may help prevent or minimize adverse health outcomes in patents receiving statin therapy.     

Hydroxymethylglutaryl-coenzyme A reductase inhibitors in osteoporosis management

OBJECTIVE: To evaluate the use and potential benefit of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) in the management of osteoporosis. DATA SOURCES: Clinical literature accessed through MEDLINE (1994-May 2001) using the key search terms HMG-CoA reductase inhibitors, statins, osteoporosis, and fractures. DATA SYNTHESIS: Osteoporosis is the most common bone disease, affecting millions of people worldwide and leading to significant morbidity and high expenditures, especially when it is not adequately managed. Recent data have documented a potential association between statin use and improvement in fracture risk profile. Therefore, an evaluation of studies investigating the effect of HMG-CoA reductase inhibitors on bone and fracture risk was conducted. CONCLUSIONS: Observational studies suggest an association between HMG-CoA reductase inhibitors and reduction in fracture risk. However, large randomized controlled studies are needed to confirm this association.     

Statins in nephrotic syndrome: a new weapon against tissue injury

The nephrotic syndrome is characterized by metabolic disorders leading to an increase in circulating lipoproteins levels. Hypertriglyceridemia and hypercholesterolemia in this case may depend on a reduction in triglyceride-rich lipoproteins catabolism and on an increase in hepatic synthesis of Apo B-containing lipoproteins. These alterations are the starting point of a self-maintaining mechanism, which can accelerate the progression of chronic renal failure. Indeed, hyperlipidemia can affect renal function, increase proteinuria and speed glomerulosclerosis, thus determining a higher risk of progression to dialysis. 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase is the rate-limiting enzyme in cholesterol synthesis from mevalonate and its inhibitors, or statins, can therefore interfere with the above-mentioned consequences of hyperlipidemia. Statins are already well known for their effectiveness on primary cardiovascular prevention, which cannot be explained only through their hypolipemic effect. As far as kidney diseases are concerned, statin therapy has been shown to prevent creatinine clearance decline and to slow renal function loss, particularly in case of proteinuria, and its favorable effect may depend only partially on the attenuation of hyperlipidemia. Statins may therefore confer tissue protection through lipid-independent mechanisms, which can be triggered by other mediators, such as angiotensin receptor blockers. Possible pathways for the protective action of statins, other than any hypocholesterolemic effect, are: cellular apoptosis/proliferation balance, inflammatory cytokines production, and signal transduction regulation. Statins also play a role in the regulation of the inflammatory and immune response, coagulation process, bone turnover, neovascularization, vascular tone, and arterial pressure. In this study, we would like to provide scientific evidences for the pleiotropic effects of statins, which could be the starting point for the development of new therapeutical strategies in different clinical areas.     

Anti-inflammatory effect of HMG-CoA reductase inhibitors

It has been suggested that HMG-CoA reductase inhibitors(statins) have additional cholesterol-independent pleiotropic effects on preventing coronary events and strokes. One of major pleiotropic actions of statins, which have been proposed, is anti-inflammatory effect. Statins have been shown to reduce infiltration of inflammatory cells into atherosclerotic lesions. It has been also reported that statins increase production of nitric oxide, reduce expression of proinflammatory cytokines and adhesion molecules, and lower plasma C-reactive protein levels. Although these effects may partially account for anti-inflammatory property of statins, its mechanisms are not fully understood. Therefore, further studies are expected to elucidate process of anti-inflammatory effect of statins.     

Treatment of childhood hypercholesterolemia with HMG-CoA reductase inhibitors

OBJECTIVE: To describe the development of coronary artery disease in childhood and review the available literature regarding the safety and efficacy of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) when used during childhood and adolescence. DATA SOURCES: A MEDLINE search was performed for the period of January 1966 through January 1999 using the key terms hypercholesterolemia, hyperlipidemia, and hydroxymethylglutaryl CoA reductase inhibitors. The search was further limited to English language, human study group, and all-child (0-18 y) age group. STUDY SELECTION AND DATA EXTRACTION: All clinical studies involving the use of HMG-CoA reductase inhibitors exclusively during childhood or adolescence were evaluated. DATA SYNTHESIS: A mean low-density lipoprotein cholesterol (LDL-C) concentration reduction of 25% can be obtained in children and adolescents treated with lovastatin, pravastatin, or simvastatin along with a lipid-lowering diet. The statins are generally well-tolerated in children and adolescents. Transient, asymptomatic elevations in creatine phosphokinase and hepatic transaminase concentrations have been reported in a small number of the children evaluated. Current data do not suggest any adverse effects on normal growth and sexual development in male adolescents, but formal evaluations have not been performed in female adolescents. CONCLUSIONS: The addition of the HMG-CoA reductase inhibitors lovastatin, pravastatin, or simvastatin to diet therapy in children > or =10 years of age may be effective when diet therapy alone has failed to obtain the recommended maximum LDL-C concentration of 130 mg/dL. The use of statins during childhood and adolescence is generally safe, but large, long-term studies should be performed before statins are routinely prescribed to children with elevated cholesterol or lipoprotein concentrations.     

Effect of fluvastatin on proteinuria in patients with immunoglobulin A nephropathy

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are established drugs for the treatment of hypercholesterolemia, but several studies have shown that benefits obtained with these drugs are not causally related only to regression of cholesterol lowering. Moreover, in experimental models of progressive renal disease, statins have reduced the extent of glomerulosclerosis. This study evaluated the antiproteinuric effect of a daily dose of 40 mg fluvastatin for 6 months in moderately proteinuric patients with immunoglobulin A nephropathy, stable renal function, and no indicators of poor long-term prognosis. The effects of therapy were evaluated on the basis of 24-hour proteinuria (total proteinuria and albuminuria), albuminemia, creatinine clearance, cholesterol, and triglyceride values. Renal function remained stable in all patients. A significant decrease in proteinuria was observed after 6 months of therapy and persisted for all the observations. An increase in serum albumin was observed after 6 months of therapy. This study suggests that there is an antiproteinuric effect of HMG-CoA reductase inhibitors in moderately proteinuric patients with immunoglobulin A nephropathy.     

New onset diabetes mellitus induced by statins: current evidence

The hydroxyl-methyl-glutaryl-coenzyme-A (HMG-CoA) reductase inhibitors of statin action are very effective and safe drugs, and they are widely used for the treatment of hyperlipidemia and the prevention of primary and secondary cardiovascular diseases (CVDs). However, recent meta-analyses of previous studies done with statins have shown that these drugs could induce new onset diabetes mellitus (NODM), especially in subjects prone to diabetes: obese, females, older age, Asian descent, and those with pre-diabetes or the metabolic syndrome. Several meta-analyses of randomized, controlled trials with statins and population-based studies of subjects taking statins have shown different incidence of NODM ranging from 28% in the JUPITER study to 43% in the UK clinical practice cohort. The exact cause of statin-induced NODM is not clearly known and several pathophysiologic mechanisms have been proposed, which include modification of the lipoprotein particle size, inhibition of HMG-CoA reductase, decreased expression of GLUT 4, and decreased adiponectin and ubiquinone levels, including others, which all lead to either increase in insulin resistance or decrease in insulin secretion. Based on the current evidence, the use of statins should not be withheld from subjects at high cardiovascular risk, even if they are prone to NODM, because their benefits outweigh their risks. However, in persons prone to the development of NODM, vigilance is required and periodic measurements of plasma glucose or HbA1c should be performed. If NODM develops, statin treatment should not be stopped, but a switch to administration of a more favorable statin, administration of statin on alternate days, or reduction of the dose should be considered, or antidiabetic therapy added.