Overexpression of lipoic acid synthase gene alleviates diabetic nephropathy of Leprdb/db mice

IntroductionDiabetic nephropathy (DN) develops in about 40% of patients with type 2 diabetes and remains the leading cause of end-stage renal disease. The mechanisms of DN remain to be elucidated. Oxidative stress is thought to be involved in the development of DN but antioxidant therapy has produced conflicting results. Therefore, we sought to define the role of antioxidant in retarding the development of DN in this study.Research design and methodsWe generated a new antioxidant/diabetes mouse model, LiasH/HLeprdb/db mice, by crossing db/db mice with LiasH/H mice, which have overexpressed Lias gene (~160%) compared with wild type, and also correspondingly increased endogenous antioxidant capacity. The new model was used to investigate whether predisposed increased endogenous antioxidant capacity was able to retard the development of DN. We systemically and dynamically examined main pathological alterations of DN and antioxidant biomarkers in blood and kidney mitochondria.ResultsLiasH/HLeprdb/db mice alleviated major pathological alterations in the early stage of DN, accompanied with significantly enhanced antioxidant defense. The model targets the main pathogenic factors by exerting multiple effects such as hypoglycemic, anti-inflammation, and antioxidant, especially protection of mitochondria.ConclusionThe antioxidant animal model is not only very useful for elucidating the underlying mechanisms of DN but also brings insight into a new therapeutic strategy for clinical applications.

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Identification of Novel Biomarker for Early Detection of Diabetic Nephropathy

Biomedicines ◽

10.3390/biomedicines9050457 ◽

2021 ◽

Vol 9 (5) ◽

pp. 457

Author(s):

Kyeong-Seok Kim ◽

Jin-Sol Lee ◽

Jae-Hyeon Park ◽

Eun-Young Lee ◽

Jong-Seok Moon ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Early Stage ◽

Kidney Injury ◽

Diabetic Patients ◽

High Morbidity ◽

Neutrophil Gelatinase Associated Lipocalin ◽

Zucker Diabetic Fatty Rats ◽

Kidney Injury Molecule 1 ◽

Stage Renal Disease ◽

End Stage

Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus. After development of DN, patients will progress to end-stage renal disease, which is associated with high morbidity and mortality. Here, we developed early-stage diagnostic biomarkers to detect DN as a strategy for DN intervention. For the DN model, Zucker diabetic fatty rats were used for DN phenotyping. The results revealed that DN rats showed significantly increased blood glucose, blood urea nitrogen (BUN), and serum creatinine levels, accompanied by severe kidney injury, fibrosis and microstructural changes. In addition, DN rats showed significantly increased urinary excretion of kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Transcriptome analysis revealed that new DN biomarkers, such as complementary component 4b (C4b), complementary factor D (CFD), C-X-C motif chemokine receptor 6 (CXCR6), and leukemia inhibitory factor (LIF) were identified. Furthermore, they were found in the urine of patients with DN. Since these biomarkers were detected in the urine and kidney of DN rats and urine of diabetic patients, the selected markers could be used as early diagnosis biomarkers for chronic diabetic nephropathy.

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MICS, an easily ignored contributor to arterial calcification in CKD patients

AJP Renal Physiology ◽

10.1152/ajprenal.00189.2016 ◽

2016 ◽

Vol 311 (4) ◽

pp. F663-F670 ◽

Cited By ~ 8

Author(s):

Kun Zhang ◽

Jingwei Gao ◽

Jie Chen ◽

Xun Liu ◽

Qingqing Cai ◽

...

Keyword(s):

Early Stage ◽

Arterial Calcification ◽

Reverse Epidemiology ◽

Multiple Risk Factors ◽

Mineral Bone Disorder ◽

Potential Strategy ◽

Underlying Mechanisms ◽

Stage Renal Disease ◽

End Stage ◽

Esrd Patients

In chronic kidney disease (CKD), simultaneous mineral and skeleton changes are prevalent, known as CKD-mineral bone disorder (CKD-MBD). Arterial calcification (AC) is a clinically important complication of CKD-MBD. It can increase arterial stiffness, which leads to severe cardiovascular events. However, current treatments have little effect on regression of AC, as its mechanisms are still unclear. There are multiple risk factors of AC, among which Malnutrition-Inflammation Complex Syndrome (MICS) is a new and crucial one. MICS, a combined syndrome of malnutrition and inflammation, generally begins at the early stage of CKD and becomes obvious in end-stage renal disease (ESRD). It was linked to reverse epidemiology and associated with increased cardiovascular mortality in ESRD patients. Recent data suggest that MICS can trigger CKD-MBD and accelerate the course of AC. In this present review, we summarize the recent understanding about the aggravating effects of MICS on AC and discuss the possible underlying mechanisms. A series of findings indicate that targeting MICS will provide a potential strategy for treating AC in CKD.

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The Role of MicroRNAs in Diabetic Nephropathy

Journal of Diabetes Research ◽

10.1155/2014/920134 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 39

Author(s):

Hao Wu ◽

Lili Kong ◽

Shanshan Zhou ◽

Wenpeng Cui ◽

Feng Xu ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Critical Role ◽

Good Prospect ◽

Protective Effects ◽

Protein Coding ◽

Diagnostic Strategies ◽

Pathogenic Factors ◽

Stage Renal Disease ◽

End Stage

Diabetic nephropathy (DN), as one of the chronic complications of diabetes, is the major cause of end-stage renal disease. However, the pathogenesis of this disease is not fully understood. In recent years, research on microRNAs (miRNAs) has become a hotspot because of their critical role in regulating posttranscriptional levels of protein-coding genes that may serve as key pathogenic factors in diseases. Several miRNAs were found to participate in the pathogenesis of DN, while others showed renal protective effects. Therefore, targeting miRNAs that are involved in DN may have a good prospect in the treatment of the disease. The aim of this review is to summarize DN-related miRNAs and provide potential targets for diagnostic strategies and therapeutic intervention.

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Huidouba Improved Podocyte Injury by Down-Regulating Nox4 Expression in Rats With Diabetic Nephropathy

Frontiers in Pharmacology ◽

10.3389/fphar.2020.587995 ◽

2020 ◽

Vol 11 ◽

Author(s):

KunBao Yang ◽

YingHui Bai ◽

Ning Yu ◽

BiNan Lu ◽

GuiYan Han ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Early Stage ◽

Fasting Blood Glucose ◽

Folk Medicine ◽

Scientific Basis ◽

Transmission Electron ◽

Podocyte Loss ◽

Stage Renal Disease ◽

End Stage

Diabetic nephropathy (DN), as the most common microvascular complication of diabetes mellitus (DM), has become one of the leading causes of end-stage renal disease (ESRD). Numerous studies have indicated that podocyte loss plays an important role in the development of DN and can even cause proteinuria in the early stage of DN. In the study, we found that Huidouba (HDB) significantly decreased the level of fasting blood glucose (FBG), the ratio of microalbumin to urine creatine (mAlb/Ucr), serum creatine (Scr), serum urea nitrogen (BUN), and malondialdehyde (MDA) in the kidney and downregulated the expression of Nox4 predominantly located in glomerular tissue while upregulating nephrin and WT1 expression in DN rats. In addition, HDB could also reduce podocyte damage and glomerular basement membrane (GBM) pathologic changes, as shown by transmission electron microscopy (TEM). In vitro study showed that HDB could inhibit high glucose (HG)-induced Reactive Oxygen Species (ROS) production and protect against podocyte apoptosis by downregulated Nox4 expression in podocytes. These results may provide a scientific basis for developing HDB as a potential folk medicine for the treatment of DN.

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Geniposide Improves Diabetic Nephropathy by Enhancing ULK1-Mediated Autophagy and Reducing Oxidative Stress through AMPK Activation

International Journal of Molecular Sciences ◽

10.3390/ijms22041651 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1651

Author(s):

Theodomir Dusabimana ◽

Eun Jung Park ◽

Jihyun Je ◽

Kyuho Jeong ◽

Seung Pil Yun ◽

...

Keyword(s):

Oxidative Stress ◽

Diabetic Nephropathy ◽

Interstitial Fibrosis ◽

Pathological Feature ◽

Protective Effects ◽

Pharmacological Agents ◽

Patients With Diabetes ◽

Underlying Mechanisms ◽

Stage Renal Disease ◽

End Stage

Diabetic nephropathy (DN) is a common pathological feature in patients with diabetes and the leading cause of end-stage renal disease. Although several pharmacological agents have been developed, the management of DN remains challenging. Geniposide, a natural compound has been reported for anti-inflammatory and anti-diabetic effects; however, its role in DN remains poorly understood. This study investigated the protective effects of geniposide on DN and its underlying mechanisms. We used a C57BL/6 mouse model of DN in combination with a high-fat diet and streptozotocin after unilateral nephrectomy and treated with geniposide by oral gavage for 5 weeks. Geniposide effectively improves DN-induced renal structural and functional abnormalities by reducing albuminuria, podocyte loss, glomerular and tubular injury, renal inflammation and interstitial fibrosis. These changes induced by geniposide were associated with an increase of AMPK activity to enhance ULK1-mediated autophagy response and a decrease of AKT activity to block oxidative stress, inflammation and fibrosis in diabetic kidney. In addition, geniposide increased the activities of PKA and GSK3β, possibly modulating AMPK and AKT pathways, efficiently improving renal dysfunction and ameliorating the progression of DN. Conclusively, geniposide enhances ULK1-mediated autophagy and reduces oxidative stress, inflammation and fibrosis, suggesting geniposide as a promising treatment for DN.

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L-carnosine and its Derivatives as New Therapeutic Agents for the Prevention and Treatment of Vascular Complications of Diabetes

Current Medicinal Chemistry ◽

10.2174/0929867326666190711102718 ◽

2020 ◽

Vol 27 (11) ◽

pp. 1744-1763 ◽

Cited By ~ 5

Author(s):

Stefano Menini ◽

Carla Iacobini ◽

Claudia Blasetti Fantauzzi ◽

Giuseppe Pugliese

Keyword(s):

Diabetic Nephropathy ◽

Life Quality ◽

Vascular Complications ◽

Carbonyl Stress ◽

Complications Of Diabetes ◽

Diabetic Vascular Complications ◽

Reactive Carbonyl Species ◽

Stage Renal Disease ◽

Stress Dependent ◽

End Stage

Vascular complications are among the most serious manifestations of diabetes. Atherosclerosis is the main cause of reduced life quality and expectancy in diabetics, whereas diabetic nephropathy and retinopathy are the most common causes of end-stage renal disease and blindness. An effective therapeutic approach to prevent vascular complications should counteract the mechanisms of injury. Among them, the toxic effects of Advanced Glycation (AGEs) and Lipoxidation (ALEs) end-products are well-recognized contributors to these sequelae. L-carnosine (β-alanyl-Lhistidine) acts as a quencher of the AGE/ALE precursors Reactive Carbonyl Species (RCS), which are highly reactive aldehydes derived from oxidative and non-oxidative modifications of sugars and lipids. Consistently, L-carnosine was found to be effective in several disease models in which glyco/lipoxidation plays a central pathogenic role. Unfortunately, in humans, L-carnosine is rapidly inactivated by serum carnosinase. Therefore, the search for carnosinase-resistant derivatives of Lcarnosine represents a suitable strategy against carbonyl stress-dependent disorders, particularly diabetic vascular complications. In this review, we present and discuss available data on the efficacy of L-carnosine and its derivatives in preventing vascular complications in rodent models of diabetes and metabolic syndrome. We also discuss genetic findings providing evidence for the involvement of the carnosinase/L-carnosine system in the risk of developing diabetic nephropathy and for preferring the use of carnosinase-resistant compounds in human disease. The availability of therapeutic strategies capable to prevent both long-term glucose toxicity, resulting from insufficient glucoselowering therapy, and lipotoxicity may help reduce the clinical and economic burden of vascular complications of diabetes and related metabolic disorders.

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Could Antioxidant Supplementation Delay Progression of Cardiovascular Disease in End-Stage Renal Disease Patients?

Current Vascular Pharmacology ◽

10.2174/1570161118666200317151553 ◽

2020 ◽

Vol 19 (1) ◽

pp. 41-54 ◽

Cited By ~ 1

Author(s):

Stefanos Roumeliotis ◽

Athanasios Roumeliotis ◽

Xenia Gorny ◽

Peter R. Mertens

Keyword(s):

Oxidative Stress ◽

Renal Disease ◽

End Stage Renal Disease ◽

Close Association ◽

Omega 3 ◽

Endstage Renal Disease ◽

Increased Risk ◽

Underlying Mechanisms ◽

Stage Renal Disease ◽

End Stage

In end-stage renal disease patients, the leading causes of mortality are of cardiovascular (CV) origin. The underlying mechanisms are complex, given that sudden heart failure is more common than acute myocardial infarction. A contributing role of oxidative stress is postulated, which is increased even at early stages of chronic kidney disease, is gradually augmented in parallel to progression to endstage renal disease and is further accelerated by renal replacement therapy. Oxidative stress ensues when there is an imbalance between reactive pro-oxidants and physiologically occurring electron donating antioxidant defence systems. During the last decade, a close association of oxidative stress with accelerated atherosclerosis and increased risk for CV and all-cause mortality has been established. Lipid peroxidation has been identified as a trigger for endothelial dysfunction, the first step towards atherogenesis. In order to counteract the deleterious effects of free radicals and thereby ameliorate, or delay, CV disease, exogenous administration of antioxidants has been proposed. Here, we attempt to summarize existing data from studies that test antioxidants for CV protection, such as vitamins E and C, statins, omega-3 fatty acids and N-acetylcysteine.

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Herba Artemisiae Capillaris Extract Prevents the Development of Streptozotocin-Induced Diabetic Nephropathy of Rat

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/5180165 ◽

2018 ◽

Vol 2018 ◽

pp. 1-13 ◽

Cited By ~ 2

Author(s):

Jianan Geng ◽

Xiaoyan Yu ◽

Chunyu Liu ◽

Chengbo Sun ◽

Menghuan Guo ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Tissue Transglutaminase ◽

Blood Lipid ◽

High Dose ◽

Oxygen Species ◽

Promising Candidate ◽

Ecm Degradation ◽

Stage Renal Disease ◽

End Stage ◽

Excessive Accumulation

Diabetic nephropathy (DN) is a major cause of end-stage renal disease throughout the world; until now there is no specific drug available. In this work, we use herba artemisiae capillaris extract (HACE) to alleviate renal fibrosis characterized by the excessive accumulation of extracellular matrix (ECM) in rats, aiming to investigate the protective effect of the HACE on DN. We found that the intragastric treatment of high-dose HACE could reverse the effect of streptozotocin not only to decrease the level of blood glucose and blood lipid in different degree but also further to improve renal functions. It is worth mentioning that the effect of HACE treatment was comparable to the positive drug benazepril. Moreover, we found that HACE treatment could on one hand inhibit oxidative stress in DN rats through regulating enzymatic activity for scavenging reactive oxygen species and on the other hand increase the ECM degradation through regulating the activity of metalloproteinase-2 (MMP-2) and the expression of tissue transglutaminase (tTG), which explained why HACE treatment inhibited ECM accumulation. On the basis of above experimental results, we conclude that HACE prevents DN development in a streptozotocin-induced DN rat model, and HACE is a promising candidate to cure DN in clinic.

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Diabetic kidney disease in thedb/dbmouse

AJP Renal Physiology ◽

10.1152/ajprenal.00315.2002 ◽

2003 ◽

Vol 284 (6) ◽

pp. F1138-F1144 ◽

Cited By ~ 267

Author(s):

Kumar Sharma ◽

Peter McCue ◽

Stephen R. Dunn

Keyword(s):

Diabetic Nephropathy ◽

Kidney Disease ◽

Mouse Model ◽

Renal Disease ◽

Mouse Models ◽

Diabetic Kidney Disease ◽

Diabetic Kidney ◽

Matrix Expansion ◽

Stage Renal Disease ◽

End Stage

Diabetic nephropathy is increasing in incidence and is now the number one cause of end-stage renal disease in the industrialized world. To gain insight into the genetic susceptibility and pathophysiology of diabetic nephropathy, an appropriate mouse model of diabetic nephropathy would be critical. A large number of mouse models of diabetes have been identified and their kidney disease characterized to various degrees. Perhaps the best characterized and most intensively investigated model is the db/ db mouse. Because this model appears to exhibit the most consistent and robust increase in albuminuria and mesangial matrix expansion, it has been used as a model of progressive diabetic renal disease. In this review, we present the findings from various studies on the renal pathology of the db/ db mouse model of diabetes in the context of human diabetic nephropathy. Furthermore, we discuss shortfalls of assessing functional renal disease in mouse models of diabetic kidney disease.

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