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The Role of Autophagy in the Pathogenesis of Diabetic Nephropathy  [PDF]
Kosuke Yamahara,Mako Yasuda,Shinji Kume,Daisuke Koya,Hiroshi Maegawa,Takashi Uzu
Journal of Diabetes Research , 2013, DOI: 10.1155/2013/193757
Abstract: Diabetic nephropathy is a leading cause of end-stage renal disease worldwide. The multipronged drug approach targeting blood pressure and serum levels of glucose, insulin, and lipids fails to fully prevent the onset and progression of diabetic nephropathy. Therefore, a new therapeutic target to combat diabetic nephropathy is required. Autophagy is a catabolic process that degrades damaged proteins and organelles in mammalian cells and plays a critical role in maintaining cellular homeostasis. The accumulation of proteins and organelles damaged by hyperglycemia and other diabetes-related metabolic changes is highly associated with the development of diabetic nephropathy. Recent studies have suggested that autophagy activity is altered in both podocytes and proximal tubular cells under diabetic conditions. Autophagy activity is regulated by both nutrient state and intracellular stresses. Under diabetic conditions, an altered nutritional state due to nutrient excess may interfere with the autophagic response stimulated by intracellular stresses, leading to exacerbation of organelle dysfunction and diabetic nephropathy. In this review, we discuss new findings showing the relationships between autophagy and diabetic nephropathy and suggest the therapeutic potential of autophagy in diabetic nephropathy. 1. Introduction The increasing prevalence of diabetes mellitus and its vascular complications has become a major health problem worldwide. Diabetic nephropathy is a serious complication of diabetes and is a common cause of end-stage renal disease. Diabetes induces glomerular damage, along with proteinuria, and subsequent tubulointerstitial lesions, leading to end-stage renal disease [1–3]. Initially, the patient shows hyperfiltration, represented by high glomerular filtration rates (GFRs) and occasional occurrence of microalbuminuria. Later, the patient shows a gradual decline in the GFR and persistence of microalbuminuria that comes before mild and subsequently moderate proteinuria. Urinary protein seems to be almost entirely reabsorbed in early and late proximal tubules and may induce tubulointerstitial damage [3]. Reducing proteinuria by keeping blood pressure and blood glucose levels under control is therefore a primary therapeutic goal with diabetic nephropathy [4, 5]. Unfortunately, however, some patients develop treatment-resistant proteinuria, resulting in end-stage renal disease. There is now an urgent need to identify new therapeutic target molecules or cellular processes that underlie the pathogenesis of diabetic nephropathy to establish additional
Role of Duration of Diabetes in the Development of Nephropathy in Type 2 Diabetic Patients  [cached]
Jiji Inassi,R Vijayalakshmy
National Journal of Medical Research , 2013,
Abstract: Introduction: Diabetes has now become the most common single cause of end stage renal disease and about 40% of diabetic patients develop nephropathy. The present study was conducted to find out the relation between duration of diabetes & development of renal disease. Methodology: The study was conducted in 120 patients with Type 2 diabetes. Three groups were selected with 40 patients in each group with diabetes of <5year duration, 5-10year duration and >10year duration. 40 normal healthy adults were included in the control group. Parameters like BP, blood urea, serum creatinine, urine microprotein were compared with controls. Results: As duration increases, there is impairment of renal function as evidenced by increase in blood urea, serum creatinine & microproteinuria. Statistically significant increase in BP was also observed with increase in duration. Both metabolic & hemodynamic factors play a decisive role in the development of nephropathy. AGEs, PDGF, TGFβ, VEGF, and Angiotensin II etc. stimulate growth & fibrotic factors leading to renal damage. Conclusion: Screening for microalbuminuria will allow early identification of patients with nephropathy. It has been shown that meticulous glycemic & bloodpressure control can slow the progression of diabetic nephropathy. Developing countries like India with its large burden of diabetes should evolve strategies for prevention of its secondary complications. [Natl J of Med Res 2013; 3(1.000): 5-8]
Prevention of Diabetic Complications by Activation of Nrf2: Diabetic Cardiomyopathy and Nephropathy  [PDF]
Bing Li,Shujun Liu,Lining Miao,Lu Cai
Journal of Diabetes Research , 2012, DOI: 10.1155/2012/216512
Abstract: Diabetic cardiomyopathy and nephropathy are two major causes of death of patients with diabetes. Extra generation of reactive oxygen species (ROS), induced by hyperglycemia, is considered as the main reason for the development of these diabetic complications. Transcription factor, NFE2-related factor 2 (Nrf2), is a master regulator of cellular detoxification response and redox status, and also provides a protective action from various oxidative stresses and damages. Recently we have demonstrated its important role in determining the susceptibility of cells or tissues to diabetes-induced oxidative stress and/or damage. Therefore, this review will specifically summarize the information available regarding the effect of Nrf2 on the diabetic complications with a focus on diabetic cardiomyopathy and nephropathy. Given the feature that Nrf2 is easily induced by several compounds, we also discussed the role of different Nrf2 activators in the prevention or therapy of various diabetic complications. These findings suggest that Nrf2 has a potential application in the clinic setting for diabetic patients in the short future. 1. Introduction Generally speaking, diabetic cardiovascular complications include macrovascular disease (e.g., stroke and atherosclerosis) and microvascular disease (e.g., retinopathy and nephropathy) [1]. Diabetic nephropathy as one of microvascular diseases and diabetic cardiomyopathy as one of macrovascular diseases are two common complications of diabetes and also two main causes of the mortality for diabetic patients. The prevention of diabetic nephropathy and cardiomyopathy has become a global concern for those who are working in diabetic care and management. Although glucose control, blood pressure, lipid lowering, and the blockade of the renin-angiotensin system [2] were used for the treatment of diabetic patients, the development and progression of nephropathy and cardiomyopathy in the patients with diabetes remains unpreventable. Therefore, to develop an effective approach to prevent or delay the development and progression of these lethal complications for diabetic patients is urgently needed. Hyperglycemia, hyperlipidemia and inflammation were three main metabolic abnormalities in diabetes, all which are able to stimulate generation of reactive oxygen or nitrogen species (ROS or RNS). Extra generation of these species is known to be critically causative of the development of diabetic complications, including diabetic nephropathy and cardiomyopathy [3–6]. Therefore, antioxidant prevention or therapy of diabetic complications has
Possible implication of LECAM-1 gene P213S polymorphism in the risk for advanced stages of diabetic nephropathy in patients with type 1 diabetes  [PDF]
Nicolae Mircea PANDURU,Danut CIMPONERIU,Pompilia APOSTOL,Maria MOTA
Analele Universitatii din Oradea, Fascicula Biologie , 2009,
Abstract: Diabetic nephropathy has an unclarified pathogenesis, with multifactorial aetiology which includes metabolic and haemodynamic abnormalities, aberrant signaling of numerous cytokines or growth factors and genetic susceptibility. Inflammation and low birth weight seems to be predisposing factors for diabetic nephropathy. In both processes levels of L-selectin (CD62L) may play an important role. The genetic heritability of diabetic nephropathy and CD62L levels sustain the investigation of relationship between LECAM polymorphisms and the disease risk. The aim of the study was to investigate a possible relationship between Pro213Ser polymorphism in LECAM-1 gene and advanced stages of diabetic nephropathy in type 1 diabetes. We enrolled unrelated Caucasian patients with type 1 diabetes mellitus, fall into control group – diabetic patients with duration of disease over 20 years without microalbuminuria (n = 83) and nephropathy group – patients with overt nephropathy or end stage renal disease – ESRD (n = 121). Pro213Ser polymorphism genotyping was achieved using PCR-RFLP technique. Genotype spread analysis indicates that ProSer and SerSer are more frequent in the nephropathy group (ProSer = 41.95% and SerSer = 6.02 %), compared with the control group (ProSer = 20.53% and SerSer = 1.73%). The corrected OR's due to the small number of patients pointed the possibility that the 213Ser is the risk allele (ORSer = 1.634; p=0.04), and 213Pro is the protective one (ORPro = 0.602; p=0.04) regarding diabetic nephropathy. Thus our results suggest a possible association between the P213S polymorphism and advanced stages of diabetic nephropathy in type 1 diabetic patients. Additional researches are required in order to acknowledge the mentioned results and to clarify the mechanism by which this polymorphism intervenes in the disease pathogenesis.
Role of toll receptors in diabetic nephropathy  [PDF]
Mona Mansour, Randa Fayez Salam, Lila Rashed, Heba Salam
Journal of Diabetes Mellitus (JDM) , 2014, DOI: 10.4236/jdm.2014.41005
Abstract:

Objectives: Diabetic nephropathy is the leading cause of chronic kidney disease. The pathogenesis of DN remains incompletely understood. It has been recently demonstrated that inflammatory processes play a significant role in the development and progression of DN. Toll-like receptors play a fundamental role in the innate immune system by triggering proinflammatory signaling pathways. Our aim is to evaluate the expression of TLRs on monocytes and relate their expression with inflammation in HD patients with & without diabetic nephropathy. Method: In a case control study (60) patients from Alkasr El Aini Hospital on hemodialysis were divided into two groups: Group 1, 30 patients on heamodialysis not due to diabetic nephropathy, Group 2, 30 patients on heamodialysis due to diabetic nephropathy, compared to Group 3, including 30 healthy controls. All participants were subjected to: Full medical history, complete physical examination, Serum creatinine, uric acid, A1C, fundus examination, detection of TLR2, TLR expression by real time PCR in peripheral blood mononuclear cells. Data were statically calculated using SPSS, comparision between groups was done using student T test comparing 2 groups, correlation using spearman’s correlation. Results: Diabetic had significantly increased TLR2, TLR4 mRNA in peripheral blood mononuclear cells compared to controls and non diabetics patient on heamodialysis (p < 0.001), TLR2, TLR4 significantly correlated with dialysis duration in diabetic (p < 0.001), no correlation with A1C in relation to TLR2 (p = 0.078), TLR4 (p = 0.163). Conclusion: TLR2, TLR4 were significantly elevated in diabetic on dialysis initiating event in the pathogenesis of DN, providing a link between hyperglycemia and hypoxia with inflammation and fibrosis within the kidney. Hence, therapeutic interventions aimed at targeting the inflammatory component through interruption of TLR signaling may be a novel strategy to target prevention and treatment of DN.

Role of Mindin in Diabetic Nephropathy  [PDF]
Maki Murakoshi,Tomohito Gohda,Mitsuo Tanimoto,Kazuhiko Funabiki,Satoshi Horikoshi,Yasuhiko Tomino
Journal of Diabetes Research , 2011, DOI: 10.1155/2011/486305
Abstract: A number of studies have shown that proinflammatory cytokines have important roles in determining the development of microvascular diabetic complications, including nephropathy. Inflammatory biomarkers should be useful for diagnosis or monitoring of diabetic nephropathy. Mindin (spondin 2) is a member of the mindin-/F-spondin family of secreted extracellular matrix (ECM) proteins. Recent studies showed that mindin is essential for initiation of innate immune response and represents a unique pattern-recognition molecule in the ECM. Previously, we demonstrated that the levels of urinary mindin in patients with type 2 diabetes were higher than those in healthy individuals. We propose that urinary mindin is a potent biomarker for the development of diabetic nephropathy. 1. Introduction Diabetic nephropathy is a major cause of end-stage kidney disease (ESKD) in the United States, Japan, and most of Europe [1]. Although the etiology of this insidious disorder is not well understood, hyperglycemia and hypertension may play pivotal roles in the pathogenesis of diabetic nephropathy. Actually, almost 30% of diabetic patients develop diabetic nephropathy despite strict blood glucose and/or blood pressure control [2]. Chronic low-grade inflammation (so-called microinflammation) has been found to play roles in the pathogenesis of diabetes [3, 4] and has been identified as a risk factor for the development of diabetes [5, 6]. Moreover, diabetes has been proposed as a disease of the innate immune system [7]. In addition, the studies in recent years have shown that inflammation and inflammatory cytokines are determinants in the development of microvascular diabetic complications such as neuropathy, retinopathy, and nephropathy [8–11]. In 1991, Hasegawa et al. reported that glomerular basement membranes from diabetic rats induced significantly greater amounts of tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1) in cultured peritoneal macrophages than when these cells were incubated with basement membranes from nondiabetic rats [12]. Based on these findings, the authors suggested for the first time that inflammatory cytokines may participate in the pathogenesis of diabetic nephropathy [12]. At present, a number of clinical studies have suggested relationships between inflammatory cytokines and diabetic nephropathy [13, 14]. Inflammatory cytokines, that is, IL-1, interleukin-6 (IL-6), and interleukin-18 (IL-18) [15, 16], vascular endothelial growth factor (VEGF) [17, 18], monocyte chemoattractant protein-1 (MCP-1) [19, 20], and transforming growth factor-β (TGF-β)
Plumbagin Ameliorates Diabetic Nephropathy via Interruption of Pathways that Include NOX4 Signalling  [PDF]
Rachel Yong, Xin-Ming Chen, Sylvie Shen, Swarna Vijayaraj, Qing Ma, Carol A. Pollock, Sonia Saad
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0073428
Abstract: NADPH oxidase 4 (Nox4) is reported to be the major source of reactive oxygen species (ROS) in the kidneys during the early stages of diabetic nephropathy. It has been shown to mediate TGFβ1-induced differentiation of cardiac fibroblasts into myofibroblasts. Despite TGFβ1 being recognised as a mediator of renal fibrosis and functional decline role in diabetic nephropathy, the renal interaction between Nox 4 and TGFβ1 is not well characterised. The aim of this study was to investigate the role of Nox4 inhibition on TGFβ1-induced fibrotic responses in proximal tubular cells and in a mouse model of diabetic nephropathy. Immortalised human proximal tubular cells (HK2) were incubated with TGFβ1 ± plumbagin (an inhibitor of Nox4) or specific Nox4 siRNA. Collagen IV and fibronectin mRNA and protein expression were measured. Streptozotocin (STZ) induced diabetic C57BL/6J mice were administered plumbagin (2 mg/kg/day) or vehicle (DMSO; 50 μl/mouse) for 24 weeks. Metabolic, physiological and histological markers of nephropathy were determined. TGFβ1 increased Nox4 mRNA expression and plumbagin and Nox4 siRNA significantly inhibited TGF-β1 induced fibronectin and collagen IV expression in human HK2 cells. STZ-induced diabetic C57BL/6J mice developed physiological features of diabetic nephropathy at 24 weeks, which were reversed with concomitant plumbagin treatment. Histologically, plumbagin ameliorated diabetes induced upregulation of extracellular matrix protein expression compared to control. This study demonstrates that plumbagin ameliorates the development of diabetic nephropathy through pathways that include Nox4 signalling.
Evaluation of role of Low Molecular Weight Heparin and Vitamin E on renal functions in patients with diabetic nephropathy
Hari Krishan Aggarwal,Deepak Jain,Sonia Sindhu,Raj Yadav
Dicle Medical Journal , 2011,
Abstract: Objectives: Diabetes has been reported to increase the risk of end stage renal disease. To prevent the progression of diabetic nephropathy (DN) search for newer approaches is warranted as diabetic patients despite good metabolic control show progressive renal damage. The aim of this study was to investigate the role of low molecular heparin (LWMH) and vitamin E in patients with diabetic nephropathy.Materials and methods: Twenty five clinically proved adult cases of DN with adequate glycemic and blood pressure control achieved with insulin or oral hypoglycemics and anti hypertensive agents (excluding ACE inhibitors and ARBs) were included. At the start of the study, patients were put on LWMH (3200 IU S/C once daily) for one month and thereafter a washout period of one month was given, following which patients received anti-oxidant vitamin-E (200mg, once daily) for three months.Results: Patients at the baseline have microalbuminuria levels ranging for 41.0 to 290.0 mg/ 24hr. One month of LMWH reduced it from 133.0±74.4 to 93.3±62.1 mg/24hr (p<0.001). Vitamin E supplementation for 3 months did not bring any statistically significant change in the values of microalbuminuria which varied from 95.2±13.0 to 94.2±12.9 mg/24hr (p>0.05). The microalbuminuria levels did not revert back to the baseline till the end of the study (5 months).Conclusion: Our results indicated that, though not a part of standard regime, LMWH treatment followed by vitamin E supplementation needs to be considered in the incipient stage of DN.
Role of T Cells in Type 2 Diabetic Nephropathy  [PDF]
Chia-Chao Wu,Huey-Kang Sytwu,Kuo-Cheng Lu,Yuh-Feng Lin
Journal of Diabetes Research , 2011, DOI: 10.1155/2011/514738
Abstract: Type 2 diabetic nephropathy (DN) is the most common cause of end-stage renal disease and is increasingly considered as an inflammatory disease characterized by leukocyte infiltration at every stage of renal involvement. Inflammation and activation of the immune system are closely involved in the pathogenesis of diabetes and its microvascular complications. Macrophage has been well recognized to play an important role in type 2 DN, leukocyte infiltration, and participated in process of DN, as was proposed recently. Th1, Th2, Th17, T reg, and cytotoxic T cells are involved in the development and progression of DN. The purpose of this review is to assemble current information concerning the role of T cells in the development and progression of type 2 DN. Specific emphasis is placed on the potential interaction and contribution of the T cells to renal damage. The therapeutic strategies involving T cells in the treatment of type 2 DN are also reviewed. Improving knowledge of the recognition of T cells as significant pathogenic mediators in DN reinforces the possibility of new potential therapeutic targets translated into future clinical treatments. 1. Introduction Diabetes mellitus (DM) is a complex syndrome characterized by absolute or relative insulin deficiency leading to hyperglycemia and an altered metabolism of glucose, fat, and protein. These metabolic dysfunctions are pathologically associated with specific microvascular diseases and various characteristic long-term complications, including diabetic neuropathy, nephropathy, and retinopathy. Diabetic nephropathy (DN), affecting more than one third of patients with type 1 DM and up to 25% of all patients with type 2 DM, is an extremely common complication of DM that profoundly contributes to patient morbidity and mortality [1–4]. Diabetic nephropathy is a leading cause of chronic kidney disease, resulting in end-stage renal disease (ESRD) which has became a major problem facing human health worldwide [1–4]. Rapidly increasing rates of DM with profound consequences of DN are the primary reason for this worldwide increase. Diabetic nephropathy (DN) is characterized as pathological findings of hypertrophy of glomerular structures, thickening of the basement membrane, and accumulation of extracellular matrix (ECM) components. Multiple mechanisms contribute to the development and outcomes of DN, such as an interaction between metabolic abnormalities, hemodynamic changes, genetic predisposition and inflammatory milieu, and oxidative stress, constituting a continuous perpetuation of injury factors for the
Role of Mindin in Diabetic Nephropathy  [PDF]
Maki Murakoshi,Tomohito Gohda,Mitsuo Tanimoto,Kazuhiko Funabiki,Satoshi Horikoshi,Yasuhiko Tomino
Experimental Diabetes Research , 2011, DOI: 10.1155/2011/486305
Abstract: A number of studies have shown that proinflammatory cytokines have important roles in determining the development of microvascular diabetic complications, including nephropathy. Inflammatory biomarkers should be useful for diagnosis or monitoring of diabetic nephropathy. Mindin (spondin 2) is a member of the mindin-/F-spondin family of secreted extracellular matrix (ECM) proteins. Recent studies showed that mindin is essential for initiation of innate immune response and represents a unique pattern-recognition molecule in the ECM. Previously, we demonstrated that the levels of urinary mindin in patients with type 2 diabetes were higher than those in healthy individuals. We propose that urinary mindin is a potent biomarker for the development of diabetic nephropathy.
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