The role of IL-18 in type 1 diabetic nephropathy: The problem and future treatment

Diabetic vascular complication is a leading cause of diabetic nephropathy, a progressive increase in urinary albumin excretion coupled with elevated blood pressure leading to declined glomerular filtration and eventually end stage renal failure. There is growing evidence that activated inflammation is contributing factor to the pathogenesis of diabetic nephropathy. Meanwhile, IL-18, a member of the IL-1 family of inflammatory cytokines, is involved in the development and progression of diabetic nephropathy. However, the benefits derived from the current therapeutics for diabetic nephropathy strategies still provide imperfect protection against renal progression. This imperfection points to the need for newer therapeutic agents that have potential to affect primary mechanisms contributing to the pathogenesis of diabetic nephropathy. Therefore, the recognition of IL-18 as significant pathogenic mediators in diabetic nephropathy leaves open the possibility of new potential therapeutic targets.     

The role of TNF-alpha in diabetic nephropathy: pathogenic and therapeutic implications

Diabetes mellitus and its complications are a public health problem. Diabetic nephropathy has become the main cause of renal failure, and furthermore is associated with a dramatic increase in cardiovascular risk. Unfortunately, the mechanisms leading to the development and progression of renal injury in diabetes are not yet fully known. There is now evidence that activated innate immunity and inflammation are relevant factors in the pathogenesis of diabetes. Furthermore, different inflammatory molecules, including pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), play a critical role in the development of microvascular diabetic complications, including nephropathy. This review discusses the role of TNF-alpha as a pathogenic factor in renal injury, focusing on diabetic nephropathy, and describes potential treatment strategies based on modulation of TNF-alpha activity.     

Nox4 and diabetic nephropathy: With a friend like this,who needs enemies?

Oxidative stress has been linked to the pathogenesis of diabetic nephropathy, a complication of diabetes in the kidney. NADPH oxidases of the Nox family are a major source of reactive oxygen species in the diabetic kidney and are critical mediators of redox signaling in glomerular and tubulointerstitial cells exposed to the diabetic milieu. Here, we present an overview of the current understanding of the roles of Nox catalytic and regulatory subunits in the processes that control mesangial cell, podocyte, and tubulointerstitial cell injury induced by hyperglycemia and other predominant factors enhanced in the diabetic milieu, including the renin–angiotensin system and transforming growth factor-β. The role of the Nox isoform Nox4 in the redox processes that alter renal biology in diabetes is highlighted.     

Comparative investigation of kidney mesangial cells from increased oxidative stress-induced diabetic rats by using different microscopy techniques

High glucose and increased oxidative stress levels are the known important mediators of diabetic nephropathy. However, the effects of these mediators on tissue damage basically due to extracellular matrix expansion in mesangial cells have yet to be fully examined within the context of early stage diabetic nephropathy. In this study, we attempted to characterize changes in mesangial cells of streptozotocin-induced diabetic rats with a comparative investigation of kidney tissue by using different microscopy techniques. The serum levels of urea and creatinine of diabetic rats, as biomarkers of kidney degeneration, decreased significantly compared to those of age-matched controls. In diabetic rats, there are increased malondialdehyde and oxidized-glutathione levels as well as reduced-glutathione and glutathione-peroxidase activity levels in renal tissue compared to those of the controls. By using light and electron microscopies, we showed that there were marked thickening in Bowman’s membrane and glomerular capillary wall, increased amount of extracellular matrix often occupying Bowman’s space, degenerations in tubules, an increased number of mesangial cells in the network of glomerular capillary walls, and increased amount of lipid accumulation in proximal tubules in the renal tissue of diabetic rats. Our confocal microscopy data confirmed also the presence of irregularity and widened in glomerular capillaries, their attachment to the Bowman’s capsule, degenerated heterochromatin, thickening in foci of glomerular basement membrane, and marked increase in mesangial cells. These results suggest that a detailed structural investigation of kidney tissue provides further information on the important role of mesangial cells in pathogenesis of diabetic nephropathy.     

Co-regulation of Gremlin and Notch signalling in diabetic nephropathy

Diabetic nephropathy is currently the leading cause of end-stage renal disease worldwide, and occurs in approximately one third of all diabetic patients. The molecular pathogenesis of diabetic nephropathy has not been fully characterized and novel mediators and drivers of the disease are still being described. Previous data from our laboratory has identified the developmentally regulated gene Gremlin as a novel target implicated in diabetic nephropathy in vitro and in vivo. We used bioinformatic analysis to examine whether Gremlin gene sequence and structure could be used to identify other genes implicated in diabetic nephropathy. The Notch ligand Jagged1 and its downstream effector, hairy enhancer of split-1 (Hes1), were identified as genes with significant similarity to Gremlin in terms of promoter structure and predicted microRNA binding elements. This led us to discover that transforming growth factor-beta (TGFbeta1), a primary driver of cellular changes in the kidney during nephropathy, increased Gremlin, Jagged1 and Hes1 expression in human kidney epithelial cells. Elevated levels of Gremlin, Jagged1 and Hes1 were also detected in extracts from renal biopsies from diabetic nephropathy patients, but not in control living donors. In situ hybridization identified specific upregulation and co-expression of Gremlin, Jagged1 and Hes1 in the same tubuli of kidneys from diabetic nephropathy patients, but not controls. Finally, Notch pathway gene clustering showed that samples from diabetic nephropathy patients grouped together, distinct from both control living donors and patients with minimal change disease. Together, these data suggest that Notch pathway gene expression is elevated in diabetic nephropathy, co-incident with Gremlin, and may contribute to the pathogenesis of this disease.     

AMPK signalling: Implications for podocyte biology in diabetic nephropathy

Diabetic nephropathy is a major long‐term complication of diabetes mellitus and one of the most common causes of end‐stage renal disease. Thickening of the glomerular basement membrane, glomerular cell hypertrophy and podocyte loss are among the main pathological changes that occur during diabetic nephropathy, resulting in proteinuria. Injury to podocytes, which are a crucial component of the glomerular filtration barrier, seems to play a key role in the development of diabetic nephropathy. Recent studies have suggested that dysregulation of AMP‐activated kinase protein, which is an essential cellular energy sensor, may play a fundamental role in this process. The purpose of this review is to highlight the molecular mechanisms associated with AMP‐activated protein kinase (AMPK) in podocytes that are involved in the pathogenesis of diabetic nephropathy.     

Upstream Regulators and Downstream Effectors of NADPH Oxidases as Novel Therapeutic Targets for Diabetic Kidney Disease

Oxidative stress has been linked to the pathogenesis of diabetic nephropathy, the complication of diabetes in the kidney. NADPH oxidases of the Nox family, and in particular the homologue Nox4, are a major source of reactive oxygen species in the diabetic kidney and are critical mediators of redox signaling in glomerular and tubulointerstitial cells exposed to the diabetic milieu. Here, we present an overview of the current knowledge related to the understanding of the role of Nox enzymes in the processes that control mesangial cell, podocyte and tubulointerstitial cell injury induced by hyperglycemia and other predominant factors enhanced in the diabetic milieu, including the renin-angiotensin system and transforming growth factor-β. The nature of the upstream modulators of Nox enzymes as well as the downstream targets of the Nox NADPH oxidases implicated in the propagation of the redox processes that alter renal biology in diabetes will be highlighted.     

糖尿病肾病发病分子机制

糖尿病肾病(DN)是高血糖所导致的一种主要的微血管并发症。在全世界糖尿病病人中,糖尿病肾病都有着非常高的发病率和致死率。并且在中国,糖尿病肾病已经成为一种常见的导致末期肾衰竭的因素。由于糖尿病肾病患者不断增多,传统的单纯通过控制血糖来控制糖尿病肾病并没有取得理想的效果,因此临床上迫切需要一些新的治疗方法来控制糖尿病肾病的发生和发展。最近的研究表明肾素-血管紧张素-醛固酮系统(RAAS)、蛋白激酶-C(PKC)、还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)氧化酶、转化生长因子-β(TGF-β)等都单独的或共同的参与了DN的发生和发展过程。这些通路彼此交叉,十分复杂,因此需要对糖尿病肾病发病分子机制进行全面的综合的理解。这篇文章旨在讨论已发现的与糖尿病肾病密切相关的分子机制以及下调通路。     

高表达C3aR的肥大细胞在糖尿病肾病患者肾组织中的分布及病理意义分析

选取糖尿病肾病(diabetic nephropathy,DN)早期、中期、晚期以及正常移植供肾各15例,分别作为DN早期组、中期组、晚期组和正常对照组,利用各个病例的肾穿刺组织标本进行C3aR免疫组化染色,分析各组中高表达C3aR浸润细胞的数量和分布特点,及其与DN发生、发展的关系,利用连续切片、免疫荧光双套色染色、免疫电镜、及甲苯胺蓝染色等方法对DN患者肾组织中高表达C3aR的浸润细胞进行细胞类型鉴定.结果表明:a.光镜和免疫电镜的形态学分析显示DN患者肾组织中高表达C3aR的浸润细胞在形态上具有肥大细胞的特点,免疫荧光双套色染色的分析显示,C3aR浸润细胞CD45阴性、CD68和类胰蛋白酶阳性,与肥大细胞的情况一致,甲苯胺蓝特殊染色进一步证实这是一种肥大细胞.b.正常移植供肾组织中虽有肥大细胞分布,但数量很少;从DN早期组到DN中期组,再到DN晚期组,肾组织中肥大细胞的数量有一种不断增加的趋势;DN患者肾组织肥大细胞的数量与24 h尿蛋白和血肌酐水平均具有很好的线性相关性.上述工作不仅揭示了在DN发生发展过程中肥大细胞在DN患者肾组织中的数量及分布情况,提示肥大细胞很可能参与了DN的发生发展过程,同时,DN患者肾组织肥大细胞高表达过敏毒素C3a受体C3aR的发现,提示C3a/C3aR通路很可能在DN患者肥大细胞的招募和激活过程中有重要作用.     

Endocannabinoids and the renal proximal tubule: An emerging role in diabetic nephropathy

Diabetic nephropathy is a leading cause for the development of end-stage renal disease. In diabetes mellitus, a number of structural changes occur within the kidney which leads to a decline in renal function. Damage to the renal proximal tubule cells (PTCs) in diabetic nephropathy includes thickening of the basement membrane, tubular fibrosis, tubular lesions and hypertrophy. A clearer understanding of the molecular mechanisms involved in the development of diabetic kidney disease is essential for the understanding of the role cellular pathways play in its pathophysiology. The endocannabinoid system is an endogenous lipid signalling system which is involved in lipogenesis, adipogenesis, inflammation and glucose metabolism. Recent studies have demonstrated that in diabetic nephropathy, there is altered expression of the endocannabinoid system. Future investigations should clarify the role of the endocannabinoid system in the development of diabetic nephropathy and within this system, identify potential therapeutics to reduce the burden of this disease.     

渐进性糖化终产物与糖尿病肾病

高级糖化终末产物(advanced glycation end product,AGE)参与了糖尿病、动脉粥样硬化、癌症等多种疾病的发生和发展,尤其是其导致的糖尿病肾病(diabetic nephropathy,DN)是终末期肾衰竭的主要病因,因此探索以AGEs为靶点的DN治疗手段成为了国内外研究的热点。本文概述了国内外关于AGE参与DN的发病机制,靶向AGE的DN治疗策略,以及天然中药基于AGE为靶点干预DN的研究进展,初步探讨了靶向AGE的DN天然药物的筛选模型。     

Mast cell modulates tumorigenesis caused by repeated bowel inflammation condition in azoxymethane/dextran sodium sulfate-induced colon cancer mouse model

Mast cells infiltrate the inflammatory microenvironment and regulate the production of many pro-inflammatory cytokines and mediators of inflammatory cell production to promote tumor development and growth in intestinal lesions. Currently, there are insufficient studies of the mediators and signaling pathways regulated by mast cells that influence the pathogenesis of colon cancer in inflamed colon tissue. This study aimed to confirm the role of mast cells in the incidence and growth of colitis-associated colon cancer (CAC) and to identify inflammation-mediated factors and signaling pathways related to tumor development. CAC was induced by the administration of azoxymethane (AOM) and dextran sodium sulfate (DSS) in mast cell-deficient (WBB6F1/J-W/W^V) and mast cell–sufficient control (WBB6F1_+/+) mice. The results confirmed that mast cell-deficient mice exhibited less tumor formation than normal mice under the same conditions, and down-regulated expression of pro-inflammatory cytokines and mediators. Mast cells play an important role in tumor formation by regulating pro-inflammatory cytokines and inflammatory mediators in CAC, indicating that they can act as new targets for the prevention and treatment of CAC.     

Klotho蛋白在糖尿病肾病中的研究进展

Klotho蛋白是近期发现的和衰老密切相关的蛋白,主要表达于肾小管上皮细胞和脑脉络膜。Klotho蛋白的高表达可以增加机体对氧化应激的抵抗。许多研究证实,在糖尿病肾病中,肾脏klotho的表达降低,并且通过调节磷酸盐代谢、抗氧化应激、抗肾脏纤维化、抗肾小球肥大、抗凋亡、抗炎症等途径保护肾功能。本文就klotho蛋白与糖尿病肾病的关系进行综述,探寻其在糖尿病肾病中的分子生物学机制。     

MTHFR gene variant is not associated with diabetic nephropathy in Japanese.

Genetic predisposition has been implicated in diabetic nephropathy. The C677T variant of the MTHFR gene has been suggested to play a role in the development of not only vascular diseases but also diabetic microangiopathies. By using polymerase chain reaction-restriction length polymorphism (PCR-RFLP) method using Hinf I, we investigated whether this variant is associated with diabetic nephropathy in Japanese. By analysing 274 unrelated Japanese patients with type II DM with or without nephropathy, there was no significant difference in the genotype distribution of this variant. The distribution of the three genotypes were not different among patients with micro- or macroalbuminuria and those without nephropathy. Although previous reports suggest a role of this variant with diabetic microangiopathies, our observations suggest that this variant is does not play an important role in the pathogenesis of diabetic nephropathy in Japanese.     

Amelioration of Diabetic Mouse Nephropathy by Catalpol Correlates with Down-Regulation of Grb10 Expression and Activation of Insulin-Like Growth Factor 1 / Insulin-Like Growth Factor 1 Receptor Signaling

Growth factor receptor-bound protein 10 (Grb10) is an adaptor protein that can negatively regulate the insulin-like growth factor 1 receptor (IGF-1R). The IGF1-1R pathway is critical for cell growth and apoptosis and has been implicated in kidney diseases; however, it is still unknown whether Grb10 expression is up-regulated and plays a role in diabetic nephropathy. Catalpol, a major active ingredient of a traditional Chinese medicine, Rehmannia, has been reported to possess anti-inflammatory and anti-aging activities and then used to treat diabetes. Herein, we aimed to assess the therapeutic effect of catalpol on a mouse model diabetic nephropathy and the potential role of Grb10 in the pathogenesis of this diabetes-associated complication. Our results showed that catalpol treatment improved diabetes-associated impaired renal functions and ameliorated pathological changes in kidneys of diabetic mice. We also found that Grb10 expression was significantly elevated in kidneys of diabetic mice as compared with that in non-diabetic mice, while treatment with catalpol significantly abrogated the elevated Grb10 expression in diabetic kidneys. On the contrary, IGF-1 mRNA levels and IGF-1R phosphorylation were significantly higher in kidneys of catalpol-treated diabetic mice than those in non-treated diabetic mice. Our results suggest that elevated Grb10 expression may play an important role in the pathogenesis of diabetic nephropathy through suppressing IGF-1/IGF-1R signaling pathway, which might be a potential molecular target of catalpol for the treatment of this diabetic complication.     

Interleukin-18 and diabetic nephropathy: A review

The inflammatory response has an important role in the pathophysiology of diabetic nephropathy that is contributed to by inflammatory mediators such as interleukin-1 (IL-1), IL-6, IL-18, tumor necrosis factor-α, and macrophage chemotactic protein-1; however, the role of IL-18 seems to be more specific than other cytokines in the inflammatory process. IL-18 is expressed in renal tissue and is upregulated by several stimuli including hyperglycemia. The expression/urinary level of IL-18 is positively correlated with the progression of diabetic nephropathy and the urinary albumin excretion rate. In this review, we have focused on the molecular pathways modulating the relationship between IL-18 and diabetic nephropathy.     

Regulation of heparanase by albumin and advanced glycation end products in proximal tubular cells

Diabetic nephropathy is one of the main causes of end-stage renal disease, in which the development of tubular damage depends on factors such as high glucose levels, albuminuria and advanced glycation end-product. In this study, we analyzed the involvement of heparanase, a heparan sulfate glycosidase, in the homeostasis of proximal tubular epithelial cells in the diabetic milieu. In vitro studies were performed on a wild-type and stably heparanase-silenced adult tubular line (HK2) and HEK293. Gene and protein expression analyses were performed in the presence and absence of diabetic mediators. Albumin and advanced glycation end-product, but not high glucose levels, increased heparanase expression in adult tubular cells via the AKT/PI3K signaling pathway. This over-expression of heparanase is then responsible for heparan sulfate reduction via its endoglycosidase activity and its capacity to regulate the heparan sulfate-proteoglycans core protein. In fact, heparanase regulates the gene expression of syndecan-1, the most abundant heparan sulfate-proteoglycans in tubular cells. We showed that heparanase is a target gene of the diabetic nephropathy mediators albumin and advanced glycation end-product, so it may be relevant to the progression of diabetic nephropathy. It could take part in several processes, e.g. extracellular-matrix remodeling and cell-cell crosstalk, via its heparan sulfate endoglycosidase activity and capacity to regulate the expression of the heparan sulfate-proteoglycan syndecan-1.     

Tumor necrosis factor-α as a therapeutic target for diabetic nephropathy

Activation of innate immunity with the subsequent development of a chronic low-grade inflammatory response is now recognized as a critical factor in the pathogenesis of diabetes mellitus and diabetic complications, including diabetic nephropathy. In the setting of diabetic nephropathy, there is now evidence of the relevant contribution of pro-inflammatory cytokines, with special participation of tumor necrosis factor-α (TNF-α). This new pathogenic perspective leads to new therapeutic implications derived from modulation of inflammation and inflammatory cytokines. Experimental studies have shown the beneficial renal actions derived from TNF-α inhibition with the use of soluble TNF-α receptor fusion proteins, chimeric monoclonal antibodies and pentoxifylline (PTF). Clinical application of this strategy is nowadays limited to PTF administration, which has demonstrated significant beneficial effects in patients with diabetic nephropathy. Overall, these studies indicate that inhibition of TNF-α might be an efficacious treatment for renal disease secondary to diabetes mellitus.     

Upregulation of cytosolic NADP+-dependent isocitrate dehydrogenase by hyperglycemia protects renal cells against oxidative stress

Hyperglycemia-induced oxidative stress is widely recognized as a key mediator in the pathogenesis of diabetic nephropathy, a complication of diabetes. We found that both expression and enzymatic activity of cytosolic NADP⁺-dependent isocitrate dehydrogenase (IDPc) were upregulated in the renal cortexes of diabetic rats and mice. Similarly, IDPc was induced in murine renal proximal tubular OK cells by high hyperglycemia, while it was abrogated by co-treatment with the antioxidant N-Acetyl-Cysteine (NAC). In OK cells, increased expression of IDPc by stable transfection prevented hyperglycemia-mediated reactive oxygen species (ROS) production, subsequent cellular oxidative stress and extracellular matrix accumulation, whereas these processes were all stimulated by decreased IDPc expression. In addition, production of NADPH and GSH in the cytosol was positively correlated with the expression level of IDPc in OK cells. These results together indicate that upregulation of IDPc in response to hyperglycemia might play an essential role in preventing the progression of diabetic nephropathy, which is accompanied by ROS-induced cellular damage and fibrosis, by providing NADPH, the reducing equivalent needed for recycling reduced glutathione and low molecular weight antioxidant thiol proteins.