scholarly journals Ventricular arrhythmias in mouse models of diabetic kidney disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kenneth R. Laurita ◽  
Shenaz Khan ◽  
Tracy McMahon ◽  
Adrienne T. Dennis ◽  
Vincent Li ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Sudden Death ◽  
Mouse Models ◽  
Diabetic Kidney Disease ◽  
Ex Vivo ◽  
Uremic Toxin ◽  
Calcium Dysregulation ◽  
Diabetic Kidney ◽  
Increased Risk ◽  
Mapping Techniques

AbstractChronic kidney disease (CKD) affects more than 20 million people in the US, and it is associated with a significantly increased risk of sudden cardiac death (SCD). Despite the significance, the mechanistic relationship between SCD and CKD is not clear and there are few effective therapies. Using optical mapping techniques, we tested the hypothesis that mouse models of progressive diabetic kidney disease (DKD) exhibit enhanced ventricular arrhythmia incidence and underlying arrhythmia substrates. Compared to wild-type mice, both Leprdb/db eNOS−/− (2KO) and high fat diet plus low dose streptozotocin (HFD + STZ) mouse models of DKD experienced sudden death and greater arrhythmia inducibility, which was more common with isoproterenol than programmed electrical stimulation. 2KO mice demonstrated slowed conduction velocity, prolonged action potential duration (APD), and myocardial fibrosis; both 2KO and HFD + STZ mice exhibited arrhythmias and calcium dysregulation with isoproterenol challenge. Finally, circulating concentrations of the uremic toxin asymmetric dimethylarginine (ADMA) were elevated in 2KO mice. Incubation of human cardiac myocytes with ADMA prolonged APD, as also observed in 2KO mice hearts ex vivo. The present study elucidates an arrhythmia-associated mechanism of sudden death associated with DKD, which may lead to more effective treatments in the vulnerable DKD patient population.

Diabetic kidney disease in thedb/dbmouse

2003 ◽  
Vol 284 (6) ◽  
pp. F1138-F1144 ◽  
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.

scholarly journals Bardoxolone methyl: drug development for diabetic kidney disease

2020 ◽  
Vol 24 (10) ◽  
pp. 857-864 ◽  
Author(s):  
Hironori Kanda ◽  
Kengo Yamawaki
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Estimated Glomerular Filtration Rate ◽  
Defense Responses ◽  
Priority Review ◽  
Phase 3 ◽  
Diabetic Kidney ◽  
Increased Risk ◽  
Phase 2 Study ◽  
First Time

Abstract Bardoxolone methyl activates the Keap1/Nrf2 system that plays an important role in defense responses against oxidative stress. Importantly, bardoxolone methyl has demonstrated increases in estimated glomerular filtration rate (eGFR) in patients with diabetic kidney disease (DKD) in clinical studies. However, an overseas Phase 3 study of bardoxolone methyl in patients with stage G4 DKD was prematurely terminated due to an increased risk for heart failure, which was considered to have been caused by early-onset fluid overload. Subsequently, a Japanese Phase 2 study demonstrated, for the first time, that bardoxolone methyl directly improves GFR, which is a true indicator of kidney function, using the inulin clearance method. In Japan, bardoxolone methyl was designated for the treatment of DKD under the Priority Review and Designation (SAKIGAKE Designation) System established by the Ministry of Health, Labour and Welfare. A Japanese Phase 3 study, with endpoints such as a ≥ 30% decrease in eGFR, is currently ongoing to assess the efficacy and safety of bardoxolone methyl in more than 1,000 patients with stages G3 and G4 DKD who have no identified risk factors.

scholarly journals Susceptibility of ApoB and PCSK9 Genetic Polymorphisms to Diabetic Kidney Disease Among Chinese Diabetic Patients

2021 ◽  
Vol 8 ◽  
Author(s):  
Liang Ma ◽  
Shaoting Wang ◽  
Hailing Zhao ◽  
Meijie Yu ◽  
Xiangling Deng ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Chinese Patients ◽  
Diabetic Patients ◽  
Diabetic Kidney ◽  
Increased Risk

This study aimed to investigate the susceptibility of 8 polymorphisms in ApoB and PCSK9 genes to diabetic kidney disease (DKD) in Chinese patients with type 2 diabetes mellitus. This is a case-control association study, including 575 DKD cases and 653 controls. Genotypes were determined using ligase detection reaction method, and data are analyzed using STATA software. The genotype distributions of rs1042034 and rs12720838 differed significantly between the two groups (P < 0.001 and P = 0.008, respectively). After adjusting for confounding factors, the mutations of rs1042034 and rs12720838 were associated with the significantly increased risk of DKD. For instance, carriers of rs1042034 T allele (CT and TT genotypes) were 1.07 times more likely to have DKD than carriers of rs1042034 CC genotype [odds ratio (OR) = 1.07, 95% confidence interval (CI): 1.03–1.10, P < 0.001]. Further, haplotype T-A-G-T in ApoB gene was overrepresented in cases (18.10%) compared with controls (12.76%) (PSimulated = 0.045), and haplotype T-A-G-T was associated with a 33% increased risk of DKD (OR = 1.33, 95% CI: 1.04, 1.70). In further haplotype-phenotype analysis, significant association was only noted for hypertension and omnibus haplotypes in ApoB gene (PSimulated = 0.001). Our findings indicate that ApoB gene is a candidate gene for DKD in Chinese patients with type 2 diabetes mellitus.

scholarly journals Role of incretin based therapies in the treatment of diabetic kidney disease

2018 ◽  
Vol 21 (5) ◽  
pp. 395-398 ◽  
Author(s):  
Paola Fioretto ◽  
Andrea Frascati
Keyword(s):  
Diabetes Mellitus ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Diabetic Kidney ◽  
Dipeptidyl Peptidase 4 ◽  
The Metabolic Syndrome ◽  
Cardiovascular Morbidity And Mortality ◽  
Increased Risk ◽  
Glucagon Like Peptide 1 ◽  
Stage Renal Disease

Diabetic kidney disease (DKD), a serious microvascular complication of diabetes mellitus is a leading cause of end-stage renal disease and is associated with an increased risk of cardiovascular morbidity and mortality. Despite advancements in blood glucose and blood pressure (BP) control, ~20% to 40% of patients with diabetes mellitus develop DKD. Intensive glycaemic and BP control positively influence decline in estimated glomerular filtration rate and albuminuria, thereby delaying the onset and progression of diabetic nephropathy. Incretin based therapies namely glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used glucose lowering agents and have shown favorable renal outcomes in DKD. This article discusses the extra-glycaemic properties of incretin based therapies and their renoprotective effects on components of the metabolic syndrome, including obesity, hypertension and dyslipidaemia; reduction in oxidative stress and inflammation; and increase in natriuresis.

scholarly journals Novel Cardiovascular Risk Factors in Patients with Diabetic Kidney Disease

2021 ◽  
Vol 22 (20) ◽  
pp. 11196
Author(s):  
Christodoula Kourtidou ◽  
Maria Stangou ◽  
Smaragdi Marinaki ◽  
Konstantinos Tziomalos
Keyword(s):  
Risk Factors ◽  
Cardiovascular Risk ◽  
Kidney Disease ◽  
Risk Stratification ◽  
Cardiovascular Risk Factors ◽  
Cardiovascular Events ◽  
Diabetic Kidney Disease ◽  
Fibroblast Growth Factor 23 ◽  
Diabetic Kidney ◽  
Increased Risk

Patients with diabetic kidney disease (DKD) are at very high risk for cardiovascular events. Only part of this increased risk can be attributed to the presence of diabetes mellitus (DM) and to other DM-related comorbidities, including hypertension and obesity. The identification of novel risk factors that underpin the association between DKD and cardiovascular disease (CVD) is essential for risk stratification, for individualization of treatment and for identification of novel treatment targets.In the present review, we summarize the current knowledge regarding the role of emerging cardiovascular risk markers in patients with DKD. Among these biomarkers, fibroblast growth factor-23 and copeptin were studied more extensively and consistently predicted cardiovascular events in this population. Therefore, it might be useful to incorporate them in risk stratification strategies in patients with DKD to identify those who would possibly benefit from more aggressive management of cardiovascular risk factors.

scholarly journals Association Between miR-30a/SNAI1 Gene Polymorphisms and the Risk of Diabetic Kidney Disease

2020 ◽  
Author(s):  
CaiLian Yang ◽  
Tao Tong ◽  
MingFang Sun ◽  
Bo Zhou
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Disease Risk ◽  
Multiple Logistic Regression Analysis ◽  
Diabetic Kidney ◽  
Increased Risk

Abstract Background: Diabetic kidney disease is a leading cause of end-stage kidney disease worldwide, its incidence is still increasing and the precise mechanism is not yet fully understood.This study aimed to investigate the possible association of miR-30a and its potential target gene, SNAI1, polymorphisms with diabetic kidney disease in patients with type 2 diabetes mellitus. Methods: This case-control is study included 240 type 2 diabetes mellitus patients with diabetic kidney disease and 280 patients without diabetic kidney disease. Genotyping of miR-30a and SNAI1 polymorphisms were performed by allelic discrimination assay with Taq-Man-MGB probes. Result: The results demonstrated that the CC genotype of rs2222722 in miR-30a was associated with an increased risk of diabetic kidney disease in Chinese type 2 diabetes mellitus patients (OR = 2.81, 95% CI 1.58-4.97, p < 0.001). Stratified analyses revealed that the miR-30a CC genotype was strongly associated with an increased risk of diabetic kidney disease in subjects who were young (< 65 years), male, and had a low body mass index, as well as those with poor glycemic control. What’s more, CC genotype carriers were more likely to exhibit decreased estimated glomerular filtration rate levels and urinary protein production. In addition, the GG genotype of SNAI1 was also associated with the development of diabetic kidney disease, and the risk was 1.73 times higher than that in AA+AG genotype carriers (95% CI 1.01-2.96, p = 0.046). Multiple logistic regression analysis showed that the miR-30a CC and SNAI1 GG genotypes were indispensable and dangerous contributing factors to the development of diabetic kidney disease. Conclusion: The CC genotype of miR-30a rs2222722 and GG genotype of SNAI1 rs1543442 might be associated with diabetic kidney disease risk in Chinese type 2 diabetes mellitus patients.

scholarly journals Association between PTX3 and PVT1 genetic polymorphisms and the risk of diabetic kidney disease in type 2 diabetic patients

2021 ◽  
Vol 33 (1) ◽  
Author(s):  
Sindhu Varghese ◽  
Gowtham Kumar Subburaj
Keyword(s):  
Kidney Disease ◽  
Genetic Polymorphisms ◽  
Diabetic Kidney Disease ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Diabetic Kidney ◽  
Increased Risk ◽  
Type 2 Diabetic

Abstract Background Very few studies have investigated the role of PTX3 and PVT1 genetic polymorphisms and their association in the progression of diabetic kidney diseases. Diabetic kidney disease (DKD) is a prominent reason of end-stage renal disease and also known to be involved in the high mortality rate of cardiovascular diseases. The current study has examined the role of PTX3 and PVT1 genetic polymorphisms in the development of diabetic kidney disease in type 2 diabetic patients. Results A significant difference between the genotypes and alleles of the rs2305619 polymorphism was observed in the diabetic patients with DKD when compared with the control group. The frequency of GG genotype was observed to be high in diabetic patients with DKD when compared to the other two groups. This specified that diabetic patients with GG genotype are at an increased risk to develop DKD. However, PVT1 (G/A) polymorphism did not show any association in the allele and genotypic frequencies with DKD when compared with T2DM and controls. Conclusion Our results propose a major influence of GG genotype of rs2305619 polymorphism to be significantly linked with an increased risk of DKD in type 2 diabetic patients.

scholarly journals Evaluation of urinary biomarkers for prediction of diabetic kidney disease: a propensity score matching analysis

2019 ◽  
Vol 10 ◽  
pp. 204201881989111
Author(s):  
Yongzhang Qin ◽  
Shuang Zhang ◽  
Xiaofang Shen ◽  
Shunming Zhang ◽  
Jingyu Wang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Kidney Disease ◽  
Propensity Score ◽  
Propensity Score Matching ◽  
Diabetic Kidney Disease ◽  
Urinary Biomarkers ◽  
Retinol Binding Protein ◽  
Cross Sectional ◽  
Diabetic Kidney ◽  
Increased Risk

Background: The aim of this study was to evaluate the diagnostic value of six urinary biomarkers for prediction of diabetic kidney disease (DKD). Methods: The cross-sectional study recruited 1053 hospitalized patients with type 2 diabetes mellitus (T2DM), who were categorized into the diabetes mellitus (DM) with normoalbuminuria (NA) group ( n = 753) and DKD group ( n = 300) according to 24-h urinary albumin excretion rate (24-h UAE). Data on the levels of six studied urinary biomarkers [transferrin (TF), immunoglobulin G (IgG), retinol-binding protein (RBP), β-galactosidase (GAL), N-acetyl-beta-glucosaminidase (NAG), and β2-microglobulin (β2MG)] were obtained. The propensity score matching (PSM) method was applied to eliminate the influences of confounding variables. Results: Patients with DKD had higher levels of all six urinary biomarkers. All indicators demonstrated significantly increased risk of DKD, except for GAL and β2MG. Single RBP yielded the greatest area under the curve (AUC) value of 0.920 compared with the other five markers, followed by TF (0.867) and IgG (0.867). However, GAL, NAG, and β2MG were shown to have a weak prognostic ability. The diagnostic values of the different combinations were not superior to the single RBP. Conclusions: RBP, TF, and IgG could be used as reliable or good predictors of DKD. The combined use of these biomarkers did not improve DKD detection.

scholarly journals Renal Effects of DPP-4 Inhibitors: A Focus on Microalbuminuria

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Martin Haluzík ◽  
Jan Frolík ◽  
Ivan Rychlík
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Cardiovascular Complications ◽  
Special Focus ◽  
Renal Effects ◽  
Diabetic Kidney ◽  
Dipeptidyl Peptidase 4 ◽  
Beneficial Effects ◽  
Increased Risk ◽  
Glucagon Like Peptide 1

Incretin-based therapies represent one of the most promising options in type 2 diabetes treatment owing to their good effectiveness with low risk of hypoglycemia and no weight gain. Other numerous potential beneficial effects of incretin-based therapies have been suggested based mostly on experimental and small clinical studies including its beta-cell- and vasculo-protective actions. One of the recently emerged interesting features of dipeptidyl peptidase-4 (DPP-4) inhibitors is its possible protective effect on the diabetic kidney disease. Here, we review the renal effects of DPP-4 inhibitors with special focus on its influence on the onset and progression of microalbuminuria, as presence of microalbuminuria represents an important early sign of kidney damage and is also associated with increased risk of hypoglycemia and cardiovascular complications. Mechanisms underlying possible nephroprotective properties of DPP-4 inhibitors include reduction of oxidative stress and inflammation and improvement of endothelial dysfunction. Effects of DPP-4 inhibitors may be both glucagon-like peptide-1 (GLP-1) dependent and independent. Ongoing prospective studies focused on the nephroprotective effects of DPP-4 inhibitors will further clarify its possible role in the prevention/attenuation of diabetic kidney disease beyond its glucose lowering properties.

scholarly journals Oxidative Stress Genes in Diabetes Mellitus Type 2: Association with Diabetic Kidney Disease

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Athanasios Roumeliotis ◽  
Stefanos Roumeliotis ◽  
Fotis Tsetsos ◽  
Marianthi Georgitsi ◽  
Panagiotis I. Georgianos ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Kidney Disease ◽  
Diabetes Mellitus Type 2 ◽  
Diabetic Kidney Disease ◽  
Diabetes Mellitus Type ◽  
Nucleotide Polymorphisms ◽  
Diabetic Kidney ◽  
Increased Risk

Diabetic type 2 patients compared to nondiabetic patients exhibit an increased risk of developing diabetic kidney disease (DKD), the leading cause of end-stage renal disease. Hyperglycemia, hypertension, oxidative stress (OS), and genetic background are some of the mechanisms and pathways implicated in DKD pathogenesis. However, data on OS pathway susceptibility genes show limited success and conflicting or inconclusive results. Our study is aimed at exploring OS pathway genes and variants which could be associated with DKD. We recruited 121 diabetes mellitus type 2 (DM2) patients with DKD (cases) and 220 DM2, non-DKD patients (control) of Greek origin and performed a case-control association study using genome-wide association data. PLINK and EIGENSOFT were used to analyze the data. Our results indicate 43 single nucleotide polymorphisms with their 21 corresponding genes on the OS pathway possibly contributing or protecting from DKD: SPP1, TPO, TTN, SGO2, NOS3, PDLIM1, CLU, CCS, GPX4, TXNRD2, EPHX2, MTL5, EPX, GPX3, ALOX12, IPCEF1, GSTA, OXR1, GPX6, AOX1, and PRNP. Therefore, a genetic OS background might underlie the complex pathogenesis of DKD in DM2 patients.

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