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Inflammation in Diabetic Nephropathy  [PDF]
Andy K. H. Lim,Gregory H. Tesch
Mediators of Inflammation , 2012, DOI: 10.1155/2012/146154
Abstract: Diabetic nephropathy is the leading cause of end-stage kidney disease worldwide but current treatments remain suboptimal. This review examines the evidence for inflammation in the development and progression of diabetic nephropathy in both experimental and human diabetes, and provides an update on recent novel experimental approaches targeting inflammation and the lessons we have learned from these approaches. We highlight the important role of inflammatory cells in the kidney, particularly infiltrating macrophages, T-lymphocytes and the subpopulation of regulatory T cells. The possible link between immune deposition and diabetic nephropathy is explored, along with the recently described immune complexes of anti-oxidized low-density lipoproteins. We also briefly discuss some of the major inflammatory cytokines involved in the pathogenesis of diabetic nephropathy, including the role of adipokines. Lastly, we present the latest data on the pathogenic role of the stress-activated protein kinases in diabetic nephropathy, from studies on the p38 mitogen activated protein kinase and the c-Jun amino terminal kinase cell signalling pathways. The genetic and pharmacological approaches which reduce inflammation in diabetic nephropathy have not only enhanced our understanding of the pathophysiology of the disease but shown promise as potential therapeutic strategies. 1. Introduction Diabetic nephropathy (DN) has not been traditionally considered an inflammatory disease. However, recent studies have shown that kidney inflammation is crucial in promoting the development and progression of DN. Inflammation may be a key factor which is activated by the metabolic, biochemical, and haemodynamic derangements known to exist in the diabetic kidney. In this paper, we discuss the evidence for inflammation in DN and the lessons we have learned from novel experimental anti-inflammatory therapies. The main areas covered include the role of immune and inflammatory cells, inflammatory cytokines, and stress-activated protein kinases. We also briefly review the controversy around the role of immune complexes and immune deposition in DN. 2. Inflammatory Cells In human DN, macrophages and T cells accumulate in the glomeruli and interstitium, even in the early stages of the disease. Recruitment of leukocytes involves three steps: (a) selectin-dependent leukocyte rolling on the endothelium, (b) chemokine-dependent integrin activation and leukocyte adhesion, and (c) transmigration of leukocytes across the endothelium [1]. Proinflammatory cytokines produced by leukocytes such as
Inflammation and Oxidative Stress in Diabetic Nephropathy: New Insights on Its Inhibition as New Therapeutic Targets  [PDF]
Akira Mima
Journal of Diabetes Research , 2013, DOI: 10.1155/2013/248563
Abstract: Diabetes and insulin resistance can greatly increase microvascular complications of diabetes including diabetic nephropathy (DN). Hyperglycemic control in diabetes is key to preventing the development and progression of DN. However, it is clinically very difficult to achieve normal glucose control in individual diabetic patients. Many factors are known to contribute to the development of DN. These include diet, age, lifestyle, or obesity. Further, inflammatory- or oxidative-stress-induced basis for DN has been gaining interest. Although anti-inflammatory or antioxidant drugs can show benefits in rodent models of DN, negative evidence from large clinical studies indicates that more effective anti-inflammatory and antioxidant drugs need to be studied to clear this question. In addition, our recent report showed that potential endogenous protective factors could decrease inflammation and oxidative stress, showing great promise for the treatment of DN. 1. Introduction Diabetes nephropathy (DN) is the major determinant of morbidity and mortality in patients with diabetes. Chronic hyperglycemia is a major initiator of DN. Several studies indicate a causal link between the degree of glycemic control in patients with diabetes and the development and progression of complications. The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive glycemic control in patients with both type 1 and 2 diabetes successfully delayed the onset and retarded macrovascular and microvascular complications including DN [1, 2]. In addition, the United Kingdom Prospective Diabetes Study (UKPDS) indicated that intensive glycemic control in patients with type 2 diabetes decreased the risk of DN and diabetic retinopathy [3, 4]. Thus, strict glycemic control could prevent the initiation and development of DN. Despite such lines of evidences conventional therapies used for glycemic control in patients with diabetes do not always prevent the ultimate progression of DN. Therefore, the use of therapies that specifically target DN could be useful and really needed in addition to a strict glycemic control. It is reported that the induction of inflammation and oxidative stress by the metabolism of hyperglycemia and dyslipidemia may play a significant role in developing vascular complications including DN in patients or animals [5–9]. The increases of inflammatory cytokines and reactive oxygen species (ROS) have also been shown in DN. Our recent studies clearly showed that insulin or glucagon-like peptide-1 (GLP-1) prevented the development of DN, neutralizing inflammation
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.
Dietary Restriction Ameliorates Diabetic Nephropathy through Anti-Inflammatory Effects and Regulation of the Autophagy via Restoration of Sirt1 in Diabetic Wistar Fatty (fa/fa) Rats: A Model of Type 2 Diabetes  [PDF]
Munehiro Kitada,Ai Takeda,Takako Nagai,Hiroki Ito,Keizo Kanasaki,Daisuke Koya
Journal of Diabetes Research , 2011, DOI: 10.1155/2011/908185
Abstract: Aim. Despite the beneficial effects of dietary restriction (DR) on lifespan, age-related diseases, including diabetes and cardiovascular diseases, its effects on type 2 diabetic nephropathy remain unknown. This study examined the renoprotective effects of DR in Wistar fatty (fa/fa) rats (WFRs). Methods. WFRs were treated with DR (40% restriction) for 24 weeks. Urinary albumin excretion, creatinine clearance, renal histologies, acetylated-NF-κB (p65), Sirt1 protein expression, and p62/Sqstm 1 accumulation in the renal cortex, as well as electron microscopic observation of mitochondrial morphology and autophagosomes in proximal tubular cells were estimated. Results. DR ameliorated renal abnormalities including inflammation in WFRs. The decrease in Sirt1 levels, increase in acetylated-NF-κB, and impaired autophagy in WFRs were improved by DR. Conclusions. DR exerted anti-inflammatory effects and improved the dysregulation of autophagy through the restoration of Sirt1 in the kidneys of WFRs, which resulted in the amelioration of renal injuries in type 2 diabetes. 1. Introduction According to the International Diabetes Federation (IDF) atlas in 2009, the estimated diabetes prevalence for 2010 has risen to 285 million, representing 6.6% of the world’s adult population, with a prediction that by 2030 the number of people with diabetes will have risen to 438 million [1]. Diabetes results in vascular changes and dysfunction, and diabetic complications are the major cause of morbidity and mortality in diabetic patients. Among diabetic vascular complications, nephropathy is a leading cause of end-stage renal disease and an independent risk factor for cardiovascular diseases. Renal inflammation is recognized as one of the important pathophysiological mechanisms and therapeutic targets for the prevention of diabetic nephropathy and atherosclerosis [2]. Dietary restriction (DR) has a variety of effects on lifespan extension and the delayed onset of age-related diseases, including cardiovascular diseases and diabetes, and is accepted as the only established antiaging experimental paradigm [3, 4]. The beneficial effects of DR involve the function of the NAD+-dependent deacetylase, Sirt1, the expression of which is induced by DR. Sirt1 has cytoprotective effects, including anti-inflammatory effects [5–7]. In addition, autophagy is a major intracellular process in which lysises in sthe damaged cytoplasmic organelles, including mitochondria, degrade protein aggregates and aged proteins [8, 9]. Although the renoprotective effects of autophagy have been shown in several
Advanced Glycation end Products, Oxidative Stress and Diabetic Nephropathy  [PDF]
Sho-ichi Yamagishi,Takanori Matsui
Oxidative Medicine and Cellular Longevity , 2010, DOI: 10.4161/oxim.3.2.11148
Abstract: About 246 million people worldwide had diabetes in 2007. The global figure of people with diabetes is projected to increase to 370 million in 2030. As the prevalence of diabetes has risen to epidemic proportions worldwide, diabetic nephropathy has become one of the most challenging health problems. Therapeutic options such as strict blood glucose and blood pressure controls are effective for preventing diabetic nephropathy, but are far from satisfactory, and the number of diabetic patients on end-stage renal disease is still increasing. Therefore, a novel therapeutic strategy that could halt the progression of diabetic nephropathy should be developed. There is accumulating evidence that advanced glycation end products (AGEs), senescent macroprotein derivatives formed at an accelerated rate under diabetes, play a role in diabetic nephropathy via oxidative stress generation. In this paper, we review the pathophysiological role of AGEs and their receptor (RAGE)-oxidative stress system in diabetic nephropathy.
Advanced Glycation end Products, Oxidative Stress and Diabetic Nephropathy  [PDF]
Sho-ichi Yamagishi,Takanori Matsui
Oxidative Medicine and Cellular Longevity , 2010, DOI: 10.4161/oxim.3.2.11148
Abstract: About 246 million people worldwide had diabetes in 2007. The global figure of people with diabetes is projected to increase to 370 million in 2030. As the prevalence of diabetes has risen to epidemic proportions worldwide, diabetic nephropathy has become one of the most challenging health problems. Therapeutic options such as strict blood glucose and blood pressure controls are effective for preventing diabetic nephropathy, but are far from satisfactory, and the number of diabetic patients on end-stage renal disease is still increasing. Therefore, a novel therapeutic strategy that could halt the progression of diabetic nephropathy should be developed. There is accumulating evidence that advanced glycation end products (AGEs), senescent macroprotein derivatives formed at an accelerated rate under diabetes, play a role in diabetic nephropathy via oxidative stress generation. In this paper, we review the pathophysiological role of AGEs and their receptor (RAGE)-oxidative stress system in diabetic nephropathy.
Peroxisome Proliferator-Activated Receptors in Diabetic Nephropathy  [PDF]
Shinji Kume,Takashi Uzu,Keiji Isshiki,Daisuke Koya
PPAR Research , 2008, DOI: 10.1155/2008/879523
Abstract: Diabetic nephropathy is a leading cause of end-stage renal disease, which is increasing in incidence worldwide, despite intensive treatment approaches such as glycemic and blood pressure control in patients with diabetes mellitus. New therapeutic strategies are needed to prevent the onset of diabetic nephropathy. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear transcription factors that play important roles in lipid and glucose homeostases. These agents might prevent the progression of diabetic nephropathy, since PPAR agonists improve dyslipidemia and insulin resistance. Furthermore, data from murine models suggest that PPAR agonists also have independent renoprotective effects by suppressing inflammation, oxidative stress, lipotoxicity, and activation of the renin-angiotensin system. This review summarizes data from clinical and experimental studies regarding the relationship between PPARs and diabetic nephropathy. The therapeutic potential of PPAR agonists in the treatment of diabetic nephropathy is also discussed.
Smoking, oxidative stress and inflammation: Impact on resting energy expenditure in diabetic nephropathy
Rajiv Agarwal
BMC Nephrology , 2005, DOI: 10.1186/1471-2369-6-13
Abstract: A case control study of 11 smokers and 24 non-smokers with overt diabetic nephropathy was performed to evaluate the chronic effect of smoking on REE. REE (indirect calorimetry), glomerular filtration rate (iothalamate clearance), markers of oxidative stress (urinary and plasma malondialdehyde (MDA), and protein carbonyls) and inflammation (C-reactive protein, tumor necrosis factor-alpha, interleukin-6) were measured on two occasions four months apart.Biomarkers of inflammation (C-reactive protein) and oxidative stress (urinary and plasma MDA) were increased in smokers. REE was increased in smokers, 24.3 kcal/kg/day compared to 21 kcal/kg/day (p = 0.009) in non-smokers. After adjusting for age, GFR, MDA, C-reactive protein, and hemoglobin A1C the difference in REE between the two groups persisted (adjusted difference 3.51 kcal/kg/d, 95% confidence interval 0.59 – 6.45, p = 0.020).Patients with overt diabetic nephropathy who smoke have a higher REE, oxidative and inflammatory state. Elevated REE is not attributable to heightened oxidative stress and inflammatory state. Smoking is an independent risk factor for elevated REE in patients with diabetic nephropathy and provides an additional mechanism by which it may lead to poor outcomes.Diabetic nephropathy is the commonest cause of end-stage renal disease (ESRD). Malnutrition in patients with ESRD is associated with increased morbidity and mortality. Nutritional decline begins long before patients with progressive CKD become dialysis dependent [1,2] which in part is related to the spontaneous reduction in dietary protein and caloric intake with reduction in glomerular filtration rate (GFR) [3-8].Recent studies point out that chronic subclinical inflammation in patients with CKD is associated with an increase in REE [9]. Other studies, done in patients without CKD, show that oxidative stress is not associated with increase in REE [10]. Smoking is associated with both an increase in oxidative stress and subclinical inflam
Therapeutic approaches to slowing the progression of diabetic nephropathy – is less best?  [cached]
Eva Vivian,Chelsea Mannebach
Drugs in Context , 2013, DOI: 10.7573/dic.212249
Abstract: Objective: Angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors are known to reduce proteinuria and have been the first-line agents in the management of diabetic nephropathy for the past 20 years. This review covers recent studies that compare the benefit of additional blockage of the renin–angiotensin–aldosterone system through combination therapy with an ACE inhibitor and ARB, or a direct renin inhibitor (DRI), to monotherapy.Design: Primary and review articles that addressed the pathophysiology, diagnosis, and therapeutic options for attenuating the progression of diabetic nephropathy were retrieved through a MEDLINE search (January 1990 to December 2012) and the bibliographies of identified articles were reviewed. English language sources were searched using the following search terms: diabetes mellitus, nephropathy, proteinuria, ACE inhibitors, ARBs, and DRIs.Setting: Randomized, placebo-controlled, short- and long-term studies published in peer-reviewed journals that were determined to be methodologically sound, with appropriate statistical analysis of the results, were selected for inclusion in this review.Participants: Adult (≥18 years) patients with diabetic nephropathy.Measurements: Serum creatinine level was used to estimate glomerular filtration rate (GFR). GFR was calculated using the four-variable Modification of Diet in Renal Disease formula. The urine albumin-to-creatinine ratio was measured at baseline and at the conclusion of each study. A value between 3.4 mg/mmol and below 33.9 mg/mmol was defined as microalbuminuria. A value of 33.9 mg/mmol or more (approximately 300 mg/g creatinine) was defined as macroalbuminuria.Results: ACE inhibitors and ARBs are now the mainstay of treatment for diabetic nephropathy. However, combination therapy with an ACE inhibitor and an ARB, or DRI, has not been found to be more effective than monotherapy with an ACE inhibitor or ARB, and may increase the risk of hyperkalemia or acute kidney injury.Conclusion: Both ACE inhibitors and ARBs remain the first-line agents in attenuating the progression of diabetic nephropathy; however, recent studies suggest that combining an ACE inhibitor with an ARB, or combining a DRI with an ACE inhibitor or ARB, may increase adverse events without clinical benefits to offset them.
MSC transplantation: a promising therapeutic strategy to manage the onset and progression of diabetic nephropathy
Marcelo E Ezquer,Fernando E Ezquer,Martha L Arango-Rodríguez,Paulette A Conget
Biological Research , 2012,
Abstract: Currently, one of the main threats to public health is diabetes mellitus. Its most detrimental complication is diabetic nephropathy (DN), a clinical syndrome associated with kidney damage and an increased risk of cardiovascular disease. Irrespective of the type of diabetes, DN follows a well-known temporal course. The earliest detectable signs are microalbuminuria and histopathological changes including extracellular matrix deposition, glomerular basement membrane thickening, glomerular and mesangial expansion. Later on macroalbuminuria appears, followed by a progressive decline in glomerular filtration rate and the loss of glomerular podocytes, tubulointerstitial fibrosis, glomerulosclerosis and arteriolar hyalinosis. Tight glycemic and hypertension controls remain the key factors for preventing or arresting the progression of DN. Nevertheless, despite considerable educational effort to control the disease, a significant number of patients not only develop DN, but also progress to chronic kidney disease. Therefore, the availability of a strategy aimed to prevent, delay or revert DN would be highly desirable. In this article, we review the pathophysiological features of DN and the therapeutic mechanisms of multipotent mesenchymal stromal cells, also referred to as mesenchymal stem cells (MSCs). The perfect match between them, together with encouraging pre-clinical data available, allow us to support the notion that MSC transplantation is a promising therapeutic strategy to manage DN onset and progression, not only because of the safety of this procedure, but mainly because of the renoprotective potential of MSCs.
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