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MicroRNA in Diabetic Nephropathy: Renin Angiotensin, AGE/RAGE, and Oxidative Stress Pathway  [PDF]
Shinji Hagiwara,Aaron McClelland,Phillip Kantharidis
Journal of Diabetes Research , 2013, DOI: 10.1155/2013/173783
Abstract: MicroRNAs (miRNA) are a novel class of small, noncoding RNA molecules that have gained the attention of many researchers in recent years due to their ability to posttranscriptionally regulate the expression of families of genes simultaneously. Their role in normal physiology and pathobiology is intriguing and their regulation in normal and disease states is fascinating. That the cells can return to a state of homeostasis when these small molecules are perturbed is truly remarkable given the multiple cellular targets of each miRNA and that many mRNAs are targeted by multiple miRNAs. Several reviews have covered aspects of miRNA function in biology and disease. Here, we review the role of miRNA in regulating the renin-angiotensin system, AGE/RAGE signalling, and under conditions of oxidative stress in the context of diabetic nephropathy. 1. Introduction The World Health Organization states that ~347 million people, roughly 9.5% of the adult population, were suffering from diabetes in 2008 [1]. The incidence of diabetes is rapidly increasing with estimates suggesting that this number will almost double by 2030. Diabetes mellitus is a major cause of chronic kidney disease (CKD) worldwide and is associated with enhanced morbidity and mortality, in particular accelerated cardiovascular disease [2, 3]. Diabetic nephropathy (DN) is now the most common cause of end-stage renal failure in the Western world [4]. Clinical associations that frequently precede overt DN are hypertension and poor glycaemic control [5], although a subset of patients develop nephropathy despite the proper glycemic control [6] and normal blood pressure. Once nephropathy is established, blood pressure often rises further, but glycaemic control can paradoxically improve as a result of reduced renal insulin clearance [7]. It is postulated that the interplay between metabolic and hemodynamic pathways plays an important role in the development and progression of DN [8] (Figure 1). Increased systemic and intraglomerular pressure is associated with increased albuminuria and glomerular injury. Activation of the renin-angiotensin-aldosterone system (RAAS) has been recognized as a key component of DN progression. Additionally, chronic hyperglycemia promotes the generation of advanced glycation end-products (AGEs). It is widely accepted that AGEs mediate their effects both directly and indirectly through receptor-dependent mechanisms. The receptor for AGE (RAGE) acts as a signal transduction receptor, and the RAGE-AGE interaction activates multiple intracellular signalling pathways which increase
Oxidative Stress/Angiotensinogen/Renin-Angiotensin System Axis in Patients with Diabetic Nephropathy  [PDF]
Masumi Kamiyama,Maki Urushihara,Takashi Morikawa,Yoshio Konishi,Masahito Imanishi,Akira Nishiyama,Hiroyuki Kobori
International Journal of Molecular Sciences , 2013, DOI: 10.3390/ijms141123045
Abstract: Although recent studies have proven that renin-angiotensin system (RAS) blockades retard the progression of diabetic nephropathy, the detailed mechanisms of their reno-protective effects on the development of diabetic nephropathy remain uncertain. In rodent models, it has been reported that reactive oxygen species (ROS) are important for intrarenal angiotensinogen (AGT) augmentation in the progression of diabetic nephropathy. However, no direct evidence is available to demonstrate that AGT expression is enhanced in the kidneys of patients with diabetes. To examine whether the expression levels of ROS- and RAS-related factors in kidneys are increased with the progression of diabetic nephropathy, biopsied samples from 8 controls and 27 patients with type 2 diabetes were used. After the biopsy, these patients were diagnosed with minor glomerular abnormality or diabetes mellitus by clinical and pathological findings. The intensities of AGT, angiotensin II (Ang II), 4-hydroxy-2-nonenal (4-HNE), and heme oxygenase-1 (HO-1) were examined by fluorescence in situ hybridization and/or immunohistochemistry. Expression levels were greater in patients with diabetes than in control subjects. Moreover, the augmented intrarenal AGT mRNA expression paralleled renal dysfunction in patients with diabetes. These data suggest the importance of the activated oxidative stress/AGT/RAS axis in the pathogenesis of diabetic nephropathy.
The Role of Adrenomedullin in the Renal NADPH Oxidase and (Pro)renin in Diabetic Mice  [PDF]
Michio Hayashi,Akihiro Tojo,Tatsuo Shimosawa,Toshiro Fujita
Journal of Diabetes Research , 2013, DOI: 10.1155/2013/134395
Abstract: Adrenomedullin has an antioxidative action and protects organs in various diseases. To clarify the role of adrenomedullin in diabetic nephropathy, we investigated the NADPH oxidase expression, renin-secreting granular cell (GC) hyperplasia, and glomerular matrix expansion in the streptozotocin (STZ)-induced diabetic adrenomedullin gene knockout (AMKO) mice compared with the STZ-diabetic wild mice at 10 weeks. The NADPH oxidase p47phox expression and lipid peroxidation products were enhanced in the glomeruli of the diabetic mice compared with that observed in the controls in both wild and AMKO mice. These changes were more obvious in the AMKO mice than in the wild mice. Glomerular mesangial matrix expansion was more severe in the diabetic AMKO mice than in the diabetic wild mice and exhibited a positive correlation with the degree of lipid peroxidation products in the glomeruli. Proteinuria was significantly higher in the diabetic AMKO mice than in the diabetic wild mice. The GC hyperplasia score and the renal prorenin expression were significantly increased in the diabetic AMKO mice than in the diabetic wild mice, and a positive correlation was observed with the NADPH oxidase expression in the macula densa. The endogenous adrenomedullin gene exhibits an antioxidant action via the inhibition of NADPH oxidase probably by suppressing the local renin-angiotensin system. 1. Introduction Adrenomedullin is a potent vasodilating peptide that is upregulated in cardiovascular diseases to counteract the disease process with its diverse physiological actions including antioxidative stress actions [1–6]. The plasma concentration of adrenomedullin also increased in the diabetic patients, and hyperglycemia increases the production of adrenomedullin in the vasculature [7, 8]. The receptors for adrenomedullin are expressed in the kidneys, especially in the glomerulus and distal nephron, and the local action of adrenomedullin is increased in diabetic rats [9], thus suggesting that adrenomedullin may contribute to the dilatation of the glomerular capillary in the early phase of diabetic nephropathy. Although the organoprotective effects of adrenomedullin have been demonstrated in various cardiovascular diseases, the mechanisms underlying its renoprotection in diabetic nephropathy are still unclear. Hyperglycemia accelerates the formation of advanced glycation end products (AGE), while also upregulating the protein kinase C (PKC) activity, accelerating the polyol pathway, and promoting sorbitol deposition [10]. These pathways are related to the increased oxidative stress,
Smoking in diabetic nephropathy: sparks in the fuel tank?  [cached]
Vishal Arvind Chakkarwar
World Journal of Diabetes , 2012, DOI: 10.4239/wjd.v3.i12.186
Abstract: Diabetic nephropathy is associated with high morbidity and mortality and the prevalence of this disease is continuously increasing worldwide. Long-term diabetes increases the likelihood of developing secondary complications like nephropathy, the most common cause of end stage renal disease. Usually, other factors like hypertension, alcoholism and smoking also partly contribute to the progression of diabetic nephropathy. Among this, cigarette smoking in diabetes has been repeatedly confirmed as an independent risk factor for the onset and progression of diabetic nephropathy. Various studies suggest that smoking is a major fuel in the development of high oxidative stress and subsequently hyperlipidemia, accumulation of advanced glycation end products, activation of the renin angiotensin system and Rho-kinase, which are observed to play a pathogenic role in the progression of diabetic nephropathy. Furthermore, cigarette smoking in diabetic patients with vascular complications produces a variety of pathological changes in the kidney, such as thickening of the glomerular basement membrane and mesangial expansion with progression in glomerulosclerosis and interstitial fibrosis, which ultimately results in end stage renal failure. Strong associations are consistently found between chronic cigarette smoking and diabetic microvascular complications. A diverse group of studies unveil potential mechanisms that may explain the role of cigarette smoking in the progression of diabetic nephropathy. Tremendous efforts are being made to control smoking mediated progression of diabetic nephropathy, but no promising therapy is yet available. The present review critically discusses the possible detrimental role of chronic cigarette smoking in the progression of diabetic nephropathy and various possible pharmacological interventions to attenuate the exacerbation of diabetic nephropathy.
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
Urinary Angiotensinogen as a Biomarker of Nephropathy in Childhood  [PDF]
Maki Urushihara,Shoji Kagami
International Journal of Nephrology , 2011, DOI: 10.4061/2011/206835
Abstract: While most circulating angiotensinogen (AGT) is synthesized in the liver, the kidneys also produce AGT. Recently, we reported that urinary AGT is mainly originated from AGT. Using newly developed human AGT ELISA, we measured urinary AGT levels in chronic glomerulonephritis (GN) patients and patients with type 1 diabetes in childhood. Urinary AGT level was positively correlated with diastolic blood pressure, urinary albumin, urinary protein levels, and urinary occult blood in chronic GN patients. Furthermore, urinary AGT level was significantly increased in chronic GN patients not treated with renin-angiotensin system (RAS) blockers compared with control subjects. Importantly, patients treated with RAS blockers had a marked attenuation of this increase. Also, urinary AGT level was significantly higher in patients with diabetic nephropathy in the premicroalbuminuric phase than in control subjects. These results suggest that urinary AGT reflects intrarenal RAS status in chronic GN and may be an early marker of diabetic nephropathy. 1. Introduction The renin-angiotensin system (RAS) plays a critical role in arterial pressure and sodium homeostasis [1]. Angiotensin II (Ang II) is the most powerful biologically active product of the RAS [2]. Recently, the focus of interest in the RAS has shifted toward the role of the local/tissue RAS in specific tissues [2]. Angiotensinogen (AGT) is the only known substrate for renin that is a rate-limiting enzyme of the RAS. Because the level of AGT is close to the Michaelis-Menten constant for renin, not only renin levels but also AGT levels can control RAS activity, and AGT upregulation may lead to elevated angiotensin peptide levels and increased blood pressure [3]. Recent studies of experimental animal models and transgenic mice have documented AGT involvement in the activation of the RAS and development of hypertension [4, 5]. Genetic manipulations that lead to AGT overexpression have consistently been shown to cause hypertension [6, 7]. In human genetic studies, a linkage has been established between the AGT gene and hypertension [8]. Enhanced intrarenal AGT mRNA and/or protein levels have also been observed in multiple experimental models of hypertension including Ang II-dependent hypertensive rats [9–12], Dahl salt-sensitive hypertensive rats [13, 14], and spontaneously hypertensive rats [15], as well as in kidney diseases including diabetic nephropathy [16–20], IgA nephropathy [21, 22], and radiation nephropathy [23]. Thus, AGT plays an important role in the development and progression of hypertension and kidney
Biochemical effects of irbesartan in experimental diabetic nephropathy  [cached]
Vaishya Richa,Singh J,Lal Harbans
Indian Journal of Pharmacology , 2009,
Abstract: Background : Diabetic nephropathy (DN) is one of the most common causes of end-stage renal failure. The pathogenesis of progressive renal damage is multifactorial and the mechanism by which hyperglycemia causes microangiopathy in diabetic glomeruli is still poorly understood. Because the renin angiotensin system has been reported to be an important contributory factor in the pathophysiology of DN, exogenous administration of angiotensin II receptor antagonist may be beneficial in counteracting some biochemical or functional changes of DN. Aims : The present study was therefore undertaken to evaluate the preventive role of irbesartan in streptozotocin (STZ)-induced DN in rats. Methods and material : STZ-induced DN in rats was assessed biochemically by measuring urine volume, protein and electrolytes as well as blood urea and creatinine clearance. Results : Marked hyperglycemia, polyuria, proteinuria and uremia along with a reduction in urine electrolytes and creatinine clearance were observed in STZ diabetic rats. Pre-treatment with irbesartan (20 mg/kg, p.o. 5 days prior to STZ and continued for 16 weeks) also significantly altered these parameters towards normal, except blood glucose. Conclusion : Pre-treatment with insulin reversed the parameters of DN. The data suggest that irbesartan prevents the development of STZ-induced DN in rats.
Angiotensin II Type II Receptor Deficiency Accelerates the Development of Nephropathy in Type I Diabetes via Oxidative Stress and ACE2  [PDF]
Shiao-Ying Chang,Yun-Wen Chen,Isabelle Chenier,Stella Le Minh Tran,Shao-Ling Zhang
Journal of Diabetes Research , 2011, DOI: 10.1155/2011/521076
Abstract: Since the functional role(s) of angiotensin II (Ang II) type II receptor (AT2R) in type I diabetes is unknown, we hypothesized that AT2R is involved in decreasing the effects of type I diabetes on the kidneys. We induced diabetes with low-dose streptozotocin (STZ) in both AT2R knockout (AT2RKO) and wild-type (WT) male mice aged 12 weeks and followed them for 4 weeks. Three subgroups nondiabetic, diabetic, and insulin-treated diabetic (Rx insulin implant) were studied. Systolic blood pressure (SBP), physiological parameters, glomerular filtration rate (GFR), renal morphology, gene expression, and apoptosis were assessed. After 4 weeks of diabetes, compared to WT controls, AT2RKO mice clearly developed features of early diabetic nephropathy (DN), such as renal hypertrophy, tubular apoptosis, and progressive extracellular matrix (ECM) protein accumulation as well as increased GFR. AT2RKO mice presented hypertension unaffected by diabetes. Renal oxidative stress (measured as heme oxygenase 1 (HO-1) gene expression and reactive oxygen species (ROS) generation) and intrarenal renin angiotensin system components, such as angiotensinogen (Agt), AT1R, and angiotensin-converting enzyme (ACE) gene expression, were augmented whereas angiotensin-converting enzyme2 (ACE2) gene expression was decreased in renal proximal tubules (RPTs) of AT2RKO mice. The renal changes noted above were significantly enhanced in diabetic AT2RKO mice but partially attenuated in insulin-treated diabetic WT and AT2RKO mice. In conclusion, AT2R deficiency accelerates the development of DN, which appears to be mediated, at least in part, via heightened oxidative stress and ACE/ACE2 ratio in RPTs. 1. Introduction Diabetic nephropathy (DN) is the single major cause of end-stage renal failure in North America [1, 2]. Among the multiple risk factors contributing to diabetic renal disease, the renin-angiotensin system (RAS), a coordinated hormonal cascade that has major physiological and pathological effects on the cardiovascular and renal functions, is one of the most important systems affecting DN development and progression [3–5]. Although chronic treatment with RAS blockers is effective in controlling hypertension and retarding DN progression, it is not a cure, indicating that the mechanisms of renal protection by RAS blockers in diabetes are far from being completely understood, and the discovery of additional therapeutic pathways as potential drug targets is of paramount importance [2, 6]. Intrarenal angiotensin II (Ang II), a principal effector of the RAS that is increased in DN, acts
Study of Angiotensin Converting Enzyme Gene Polymorphism in Egyptian Type 2 Diabetes Mellitus with Diabetic Kidney Disease  [PDF]
Rizk A. El-baz, Alaa M. Wafa, El-Shaimaa Marrawan, Ahmed Ragab A. El-Tawab, Zeinab Ibraheam Aly
International Journal of Clinical Medicine (IJCM) , 2018, DOI: 10.4236/ijcm.2018.98053
Abstract: Objective: Diabetic kidney disease DKD (Diabetic nephropathy DN) is considered one of the chronic micro vascular complications of diabetes mellitus and considered the commonest cause leading to chronic renal failure and chronic renal dialysis. Genetic susceptibility has been implicated in DKD. The angiotensin converting enzyme (ACE) is one of the key roles in the renin angiotensin system cascade by converting angiotensin I to angiotensin II which plays a key role in regulation of blood pressure as well as electrolytes and fluid balance. This study addressed the association of (ACE) gene polymorphisms with DN in Egyptian (T2DM) patients. Methods: Our research comprised of 75 cases of T2DM with diabetic kidney disease, 100 cases of T2DM without DKD and 94 healthy volunteers. Different genotypes of ACE gene were determined by SSP-PCR analysis. Results: Gene polymorphism of ACE (DD, ID, II) in diabetic patient with DKD is 44%, 52%, 4% respectively and for T2DM individuals without DKD is 23%, 72%, 5% respectively. (DD) had significant higher frequencies in T2DM patients with DKD compared to those without DKD (p < 0.005) and (ID) had significant higher frequencies in T2DM without DKD (p < 0.0001). These results indicated that there is an association between ACE gene polymorphisms and susceptibility of diabetic patients to be affected by diabetic kidney disease. Conclusion: From our results, we can conclude that genotype of ACE in Egypt DD is the genotype of cases diabetic kidney disease. So the presence of D allele has a significant relation with diabetic kidney disease. Our data confirm the role of ACE in its relationship with diabetic kidney disease in Egyptian type 2 diabetic patients.
Inhibition of renin activity by aliskiren ameliorates diabetic nephropathy in type 1 diabetes mouse model  [PDF]
Yan Zhang, Youli Wang, Yunzi Chen, Dilip K. Deb, Tao Sun, Qun Zhao, Yan Chun Li
Journal of Diabetes Mellitus (JDM) , 2012, DOI: 10.4236/jdm.2012.23055
Abstract: Renin is the rate-limiting enzyme of the reninangiotensin system (RAS). In addition to its enzymatic activity to generate angiotensin I, renin also signals through the (pro)renin receptor to exert angiotensin II-independent effects. In this study we examined the effect of renin inhibition on the development of diabetic nephropathy. Male DBA/2J mice were induced to diabetes with streptozotocin, and the diabetic mice were treated for 16 weeks with saline or aliskiren, a renin enzymatic inhibitor. Aliskiren treatment had little effects on blood glucose and blood pressure in diabetic mice. Saline-treated mice developed progressive albuminuria and glome-rulosclerosis, and aliskiren treatment effectively alleviated albumiuria and glomerulosclerosis. Morphologically aliskiren treatment prevented the thickening of the glomerular basement membrane and reduced podocyte loss. At the molecular levels, aliskiren prevented the decline of slit diaphragm proteins and blocked the synthesis of extracellular matrix and pro-fibrotic factors in the diabetic kidney. Aliskiren treatment results in compensatory renin increase in the glomeruli due to blockade of the negative feedback loop, and also partially suppressed the intracellular signaling mediated by the (pro)renin receptor activated in hyperglycemia. These observations suggest that the therapeutic activity of aliskiren to prevent diabetic renal injury is contributed by inhibition of both the angiotensin II-dependent and -independent pathways. Taken together, it is concluded that inhibition of renin enzymatic activity ameliorates diabetic renal injury in type 1 diabetes, and support the use of aliskiren in diabetes kidney disease.
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