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Autophagy as a Therapeutic Target in Diabetic Nephropathy
Yuki Tanaka,Shinji Kume,Munehiro Kitada,Keizo Kanasaki,Takashi Uzu,Hiroshi Maegawa,Daisuke Koya
Experimental Diabetes Research , 2012, DOI: 10.1155/2012/628978
Abstract: Diabetic nephropathy is a serious complication of diabetes mellitus, and its prevalence has been increasing worldwide. Therefore, there is an urgent need to identify a new therapeutic target to prevent diabetic nephropathy. Autophagy is a major catabolic pathway involved in degrading and recycling macromolecules and damaged organelles to maintain intracellular homeostasis. The study of autophagy in mammalian systems is advancing rapidly and has revealed that it is involved in the pathogenesis of various metabolic or age-related diseases. The functional role of autophagy in the kidneys is also currently under intense investigation although, until recently, evidence showing the involvement of autophagy in the pathogenesis of diabetic nephropathy has been limited. We provide a systematic review of autophagy and discuss the therapeutic potential of autophagy in diabetic nephropathy to help future investigations in this field.
Autophagy Attenuates Diabetic Glomerular Damage through Protection of Hyperglycemia-Induced Podocyte Injury  [PDF]
Li Fang, Yang Zhou, Hongdi Cao, Ping Wen, Lei Jiang, Weichun He, Chunsun Dai, Junwei Yang
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0060546
Abstract: Despite the recent attention focused on the important role of autophagy in maintaining podocyte homeostasis, little is known about the changes and mechanisms of autophagy in podocyte dysfunction under diabetic condition. In this study, we investigated the role of autophagy in podocyte biology and its involvement in the pathogenesis of diabetic nephropathy. Podocytes had a high basal level of autophagy. And basal autophagy inhibition either by 3-methyladenenine (3-MA) or by Beclin-1 siRNA was detrimental to its architectural structure. However, under diabetic condition in vivo and under high glucose conditions in vitro, high basal level of autophagy in podocytes became defective and defective autophagy facilitated the podocyte injury. Since the dynamics of endoplasmic reticulum(ER) seemed to play a vital role in regulating the autophagic flux, the results that Salubrinal/Tauroursodeoxycholic acid (TUDCA) could restore defective autophagy further indicated that the evolution of autophagy may be mediated by the changes of cytoprotective output in the ER stress. Finally, we demonstrated in vivo that the autophagy of podocyte was inhibited under diabetic status and TUDCA could improve defective autophagy. Taken together, these data suggested that autophagy might be interrupted due to the failure of ER cytoprotective capacity upon high glucose induced unmitigated stress, and the defective autophagy might accelerate the irreparable progression of diabetic nephropathy.
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)
Cytokines and T Helper Cells in Diabetic Nephropathy Pathogenesis  [PDF]
Liliane Silvano Araújo, Marcos Vinícius da Silva, Crislaine Aparecida da Silva, Maria Luiza Reis Monteiro, Lívia Helena de Morais Pereira, Laura Penna Rocha, Rosana Rosa Miranda Corrêa, Marlene Ant?nia Reis, Juliana Reis Machado
Journal of Diabetes Mellitus (JDM) , 2016, DOI: 10.4236/jdm.2016.64025
Abstract: Diabetic Nephropathy (DN) is considered the main cause of end stage kidney disease around the world. However, its pathogenesis is not completely established. More than just a direct consequence of chronic glycemic changes, recent studies had suggested Diabetic Nephropathy could be considered an inflammatory disease. It has been shown that concentrations of pro-inflammatory cytokines, as IL-1, IL-6, IL-18, IL-33, IFN-γ and TNF-α actively participate in development and progression of DN, and thus, are involved in pathogenesis. Besides, changes in acquired immune response, especially the presence of cellular immune response profiles of pro-inflammatory and effector nature, mainly Th1 and Th17, as the imbalance between interaction of cytokines and T regulatory cells, foment the onset and progression of DN. Here we summarize the main evidences that support the critical role of the immune system in this condition. These new conceptual advances in DN understanding are essential for development of new the rapeutical strategies and prognostic factors, which could be protagonists or adjuvants to the current ones, leading ultimately to a better clinical management of DN patients.
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
Diabetic Nephropathy
Armagan TUGRUL
Trakya Universitesi Tip Fakultesi Dergisi , 2002,
Abstract: Diabetic nephropathy is an important cause of end-stage renal disease. Its incidence is closely correlated with the duration of diabetes mellitus. Hyperglycemia, hypertension, smoking, advanced age, insulin resistance, male gender, high protein intake, and genetic factors have been implicated in the development of diabetic nephropathy. It has been shown that non-enzymatic protein glycation, enhanced polyol pathway, increased protein kinase C activity, glucose toxicity, biochemical defects in the extracellular matrix, and genetic factors play role in its pathogenesis. Treatment of diabetic nephropathy includes good blood glucose regulation with insulin, treatment of hypertension and microalbuminuria with ACE inhibitors, and decreased protein intake.
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.
Role of metabolic control on diabetic nephropathy
Macedo, Célia Sperandéo;Capelletti, Sonia Maria;Mercadante, Maria Cecília Salgado;Padovani, Carlos Roberto;Spadella, César Tadeu;
Acta Cirurgica Brasileira , 2002, DOI: 10.1590/S0102-86502002000600003
Abstract: objective: the aim of this investigation was studying the influence of glucose metabolic control on diabetic nephropathy. the authors observed the effect of acarbose, insulin, and both drugs on the metabolic control and development of mesangial enlargement of kidney glomeruli in alloxan-diabetic rats. methods: five groups of wistar rats were used: normal rats (n), non-treated alloxan-diabetic rats (d), alloxan-diabetic rats treated with acarbose (ad), alloxan-diabetic rats treated with insulin (id), and alloxan-diabetic rats treated with insulin plus acarbose (iad). the following parameters were evaluated: body weight; water and food intake; diuresis; blood and urine glucose levels; and the kidney lesions: mesangial enlargement and tubule cell vacuolization. renal lesions were analysed using a semi-quantitative score 1, 3, 6, 9, and 12 months after diabetes induction. results: diabetic rats showed a marked increase of glycemia, urinary glucose levels, diuresis, water and food intake, and weight loss, while the treated diabetic rats showed significant decreased levels of these parameters. the most satisfactory metabolic control was that of diabetic rats treated with acarbose + insulin. there was a significant mesangial enlargement in diabetic rats compared to normal rats from the third up to the 12th month after diabetes induction, with a significant difference between the animals treated with acarbose + insulin and non-treated diabetic rats. a difference between the animals treated with acarbose or insulin alone and non-treated diabetics rats was not seen. conclusions: the authors discuss the results stressing the role of diabetic metabolic control in the prevention of diabetic nephropathy.
Role of metabolic control on diabetic nephropathy  [cached]
Macedo Célia Sperandéo,Capelletti Sonia Maria,Mercadante Maria Cecília Salgado,Padovani Carlos Roberto
Acta Cirurgica Brasileira , 2002,
Abstract: OBJECTIVE: The aim of this investigation was studying the influence of glucose metabolic control on diabetic nephropathy. The authors observed the effect of acarbose, insulin, and both drugs on the metabolic control and development of mesangial enlargement of kidney glomeruli in alloxan-diabetic rats. METHODS: Five groups of Wistar rats were used: normal rats (N), non-treated alloxan-diabetic rats (D), alloxan-diabetic rats treated with acarbose (AD), alloxan-diabetic rats treated with insulin (ID), and alloxan-diabetic rats treated with insulin plus acarbose (IAD). The following parameters were evaluated: body weight; water and food intake; diuresis; blood and urine glucose levels; and the kidney lesions: mesangial enlargement and tubule cell vacuolization. Renal lesions were analysed using a semi-quantitative score 1, 3, 6, 9, and 12 months after diabetes induction. RESULTS: Diabetic rats showed a marked increase of glycemia, urinary glucose levels, diuresis, water and food intake, and weight loss, while the treated diabetic rats showed significant decreased levels of these parameters. The most satisfactory metabolic control was that of diabetic rats treated with acarbose + insulin. There was a significant mesangial enlargement in diabetic rats compared to normal rats from the third up to the 12th month after diabetes induction, with a significant difference between the animals treated with acarbose + insulin and non-treated diabetic rats. A difference between the animals treated with acarbose or insulin alone and non-treated diabetics rats was not seen. CONCLUSIONS: The authors discuss the results stressing the role of diabetic metabolic control in the prevention of diabetic nephropathy.
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