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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 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.
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 the renin angiotensin system in diabetic nephropathy  [cached]
Tanuj Chawla,Deepika Sharma,Archana Singh
World Journal of Diabetes , 2010,
Abstract: Diabetic nephropathy has been the cause of lot of morbidity and mortality in the diabetic population. The renin angiotensin system (RAS) is considered to be involved in most of the pathological processes that result in diabetic nephropathy. This system has various subsystems which contribute to the disease pathology. One of these involves angiotensin II (Ang II) which shows increased activity during diabetic nephropathy. This causes hypertrophy of various renal cells and has a pressor effect on arteriolar smooth muscle resulting in increased vascular pressure. Ang II also induces inflammation, apoptosis, cell growth, migration and differentiation. Monocyte chemoattractant protein-1 production responsible for renal fibrosis is also regulated by RAS. Polymorphism of angiotensin converting enzyme (ACE) and Angiotensinogen has been shown to have effects on RAS. Available treatment modalities have proven effective in controlling the progression of nephropathy. Various drugs (based on antagonism of RAS) are currently in the market and others are still under trial. Amongst the approved drugs, ACE inhibitors and angiotensin receptor blockers (ARBs) are widely used in clinical practice. ARBs are shown to be superior to ACE inhibitors in terms of reducing proteinuria but the combined role of ARBs with ACE inhibitors in diabetic nephropathy is under debate.
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 T Cells in Type 2 Diabetic Nephropathy  [PDF]
Chia-Chao Wu,Huey-Kang Sytwu,Kuo-Cheng Lu,Yuh-Feng Lin
Experimental 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.
Pathophysiological role and therapeutic implications of inflammation in diabetic nephropathy  [cached]
Desirée Luis-Rodríguez,Alberto Martínez-Castelao,José Luis Górriz,Fernando de álvaro
World Journal of Diabetes , 2012, DOI: 10.4239/wjd.v3.i1.7
Abstract: Diabetes mellitus and its complications are becoming one of the most important health problems in the world. Diabetic nephropathy is now the main cause of end-stage renal disease. The mechanisms leading to the development and progression of renal injury are not well known. Therefore, it is very important to find new pathogenic pathways to provide opportunities for early diagnosis and targets for novel treatments. At the present time, we know that activation of innate immunity with development of a chronic low grade inflammatory response is a recognized factor in the pathogenesis of diabetic nephropathy. Numerous experimental and clinical studies have shown the participation of different inflammatory molecules and pathways in the pathophysiology of this complication.
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]
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.
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