scholarly journals Metabolomics in Diabetic Kidney Disease: Unraveling the Biochemistry of a Silent Killer

2016 ◽  
Vol 44 (2) ◽  
pp. 92-103 ◽  
Author(s):  
Manjula Darshi ◽  
Benjamin Van Espen ◽  
Kumar Sharma
Keyword(s):  
Kidney Disease ◽  
Small Molecules ◽  
Animal Studies ◽  
Large Scale ◽  
Diabetic Kidney Disease ◽  
Acid Oxidation ◽  
Treatment Interventions ◽  
Diabetic Kidney ◽  
Bioinformatic Tools ◽  
Large Scale Analysis

The development of new therapies for chronic diseases, such as diabetic kidney disease (DKD), will continue to be hampered by lack of sufficient biomarkers that will provide insights and will be responsive to treatment interventions. The recent application of metabolomic technologies, such as nuclear magnetic resonance and mass spectroscopy, has allowed large-scale analysis of small molecules to be interrogated in a targeted or untargeted manner. Recent advances from both human and animal studies that have arisen from metabolomic analysis have recognized that mitochondrial function and fatty acid oxidation play key roles in the development and progression of DKD. Although many challenges in the technology for clinical chronic kidney disease (CKD) are yet to be validated, there will very likely be ongoing major contributions of metabolomics to develop new biochemical understanding for diabetic and CKD. The clinical application of metabolomics and accompanying bioinformatic tools will likely be a cornerstone of personalized medicine triumphs for CKD.

scholarly journals The New and the Old: Platform Cross-Validation of Immunoaffinity MASS Spectrometry versus ELISA for PromarkerD, a Predictive Test for Diabetic Kidney Disease

Proteomes ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 31
Author(s):  
Scott Bringans ◽  
Kirsten Peters ◽  
Tammy Casey ◽  
Jason Ito ◽  
Richard Lipscombe
Keyword(s):  
Mass Spectrometry ◽  
Kidney Disease ◽  
Large Scale ◽  
Diabetic Kidney Disease ◽  
Clinical Laboratory ◽  
Predictive Test ◽  
Protein Biomarkers ◽  
Diabetic Kidney ◽  
Technology Platforms ◽  
Mass Spectrometry Assay

PromarkerD is a proteomics derived test for predicting diabetic kidney disease that measures the concentrations of three plasma protein biomarkers, APOA4, CD5L and IBP3. Antibodies against these proteins were developed and applied to a multiplexed immunoaffinity capture mass spectrometry assay. In parallel, and facilitating current clinical laboratory workflows, a standard ELISA was also developed to measure each protein. The performance characteristics of the two technology platforms were compared using a cohort of 100 samples, with PromarkerD test scores demonstrating a high correlation (R = 0.97). These technologies illustrate the potential for large scale, high throughput clinical applications of proteomics now and into the future.

scholarly journals Metformin Protects against Podocyte Injury in Diabetic Kidney Disease

2020 ◽  
Vol 13 (12) ◽  
pp. 452
Author(s):  
Sanna Lehtonen
Keyword(s):  
Kidney Disease ◽  
Animal Studies ◽  
Diabetic Kidney Disease ◽  
Clinical Settings ◽  
Low Grade ◽  
Diabetic Kidney ◽  
Cellular Targets ◽  
Glomerular Epithelial Cells ◽  
Low Grade Inflammation

Metformin is the most commonly prescribed drug for treating type 2 diabetes mellitus (T2D). Its mechanisms of action have been under extensive investigation, revealing that it has multiple cellular targets, either direct or indirect ones, via which it regulates numerous cellular pathways. Diabetic kidney disease (DKD), the serious complication of T2D, develops in up to 50% of the individuals with T2D. Various mechanisms contribute to the development of DKD, including hyperglycaemia, dyslipidemia, oxidative stress, chronic low-grade inflammation, altered autophagic activity and insulin resistance, among others. Metformin has been shown to affect these pathways, and thus, it could slow down or prevent the progression of DKD. Despite several animal studies demonstrating the renoprotective effects of metformin, there is no concrete evidence in clinical settings. This review summarizes the renoprotective effects of metformin in experimental settings. Special emphasis is on the effects of metformin on podocytes, the glomerular epithelial cells that are central in maintaining the glomerular ultrafiltration function.

scholarly journals Mitochondrial DNA: A New Predictor of Diabetic Kidney Disease

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Yajing Huang ◽  
Jingwei Chi ◽  
Fanxiang Wei ◽  
Yue Zhou ◽  
Yihai Cao ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mitochondrial Dysfunction ◽  
Large Scale ◽  
Diabetic Kidney Disease ◽  
Endothelial Damage ◽  
Inflammatory Factors ◽  
Mtdna Copy Number ◽  
Diabetic Kidney ◽  
Patients With Diabetes ◽  
Stage Renal Disease

Diabetic kidney disease (DKD) is a common cause of end-stage renal disease, and diagnosis and treatment in time can help delay its progress. At present, there are more and more studies on the pathogenesis of DKD; mitochondrial dysfunction plays an important role in DKD. The occurrence and development of DKD is closely related to epigenetic changes and the interaction between mtDNA, ROS, inflammatory factors, and endothelial damage, which continuously aggravates kidney. The change of mtDNA is both the cause of DKD and the result of DKD. It is of great significance to incorporate the change of mtDNA into the monitoring of patients with diabetes. Existing evidence indicates that changes in mtDNA copy number in blood and urine reflect mitochondrial dysfunction and the severity of DKD. However, large-scale, long-term follow-up clinical trials are still needed to determine the threshold range. By the time, mitochondrial-targeted antioxidants will become a new method for the treatment of DKD and other diabetic complications; mtDNA also can be a therapeutic target for them.

scholarly journals Connectivity mapping of glomerular proteins identifies dimethylaminoparthenolide as a new inhibitor of diabetic kidney disease

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Julie Klein ◽  
Cécile Caubet ◽  
Mylène Camus ◽  
Manousos Makridakis ◽  
Colette Denis ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Large Scale ◽  
Diabetic Kidney Disease ◽  
Enzyme Inhibitor ◽  
Oral Treatment ◽  
Drug Repurposing ◽  
Water Soluble ◽  
Diabetic Patients ◽  
Diabetic Kidney ◽  
Connectivity Mapping

Abstract While blocking the renin angiotensin aldosterone system (RAAS) has been the main therapeutic strategy to control diabetic kidney disease (DKD) for many years, 25–30% of diabetic patients still develop the disease. In the present work we adopted a systems biology strategy to analyze glomerular protein signatures to identify drugs with potential therapeutic properties in DKD acting through a RAAS-independent mechanism. Glomeruli were isolated from wild type and type 1 diabetic (Ins2Akita) mice treated or not with the angiotensin-converting enzyme inhibitor (ACEi) ramipril. Ramipril efficiently reduced the urinary albumin/creatine ratio (ACR) of Ins2Akita mice without modifying DKD-associated renal-injuries. Large scale quantitative proteomics was used to identify the DKD-associated glomerular proteins (DKD-GPs) that were ramipril-insensitive (RI-DKD-GPs). The raw data are publicly available via ProteomeXchange with identifier PXD018728. We then applied an in silico drug repurposing approach using a pattern-matching algorithm (Connectivity Mapping) to compare the RI-DKD-GPs’s signature with a collection of thousands of transcriptional signatures of bioactive compounds. The sesquiterpene lactone parthenolide was identified as one of the top compounds predicted to reverse the RI-DKD-GPs’s signature. Oral treatment of 2 months old Ins2Akita mice with dimethylaminoparthenolide (DMAPT, a water-soluble analogue of parthenolide) for two months at 10 mg/kg/d by gavage significantly reduced urinary ACR. However, in contrast to ramipril, DMAPT also significantly reduced glomerulosclerosis and tubulointerstitial fibrosis. Using a system biology approach, we identified DMAPT, as a compound with a potential add-on value to standard-of-care ACEi-treatment in DKD.

scholarly journals Pentoxifylline in diabetic kidney disease (VA PTXRx): protocol for a pragmatic randomised controlled trial

BMJ Open ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. e053019
Author(s):  
David J Leehey ◽  
Kimberly Carlson ◽  
Domenic J Reda ◽  
Ian Craig ◽  
Christina Clise ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Usual Care ◽  
Large Scale ◽  
Diabetic Kidney Disease ◽  
Controlled Trial ◽  
Scientific Journal ◽  
Phosphodiesterase Inhibitor ◽  
Major Adverse Cardiovascular Events ◽  
Diabetic Kidney ◽  
Study Results

IntroductionDiabetic kidney disease (DKD) is the most frequent cause of end-stage renal disease (ESRD) in the USA and worldwide. Recent experimental and clinical data suggest that the non-specific phosphodiesterase inhibitor pentoxifylline (PTX) may decrease progression of chronic kidney disease. However, a large-scale randomised clinical trial is needed to determine whether PTX can reduce ESRD and death in DKD.Methods and analysisVeterans Affairs (VA) PTXRx is a pragmatic, randomised, placebo-controlled multicentre VA Cooperative Study to test the hypothesis that PTX, when added to usual care, leads to a reduction in the time to ESRD or death in patients with type 2 diabetes with DKD when compared with usual care plus placebo. The study aims to enrol 2510 patients over a 4-year period with an additional up to 5-year follow-up to generate a total of 646 primary events. The primary objective of this study is to compare the time until ESRD or death (all-cause mortality) between participants randomised to PTX or placebo. Secondary endpoints will be: (1) health-related quality of life, (2) time to doubling of serum creatinine, (3) incidence of hospitalisations for congestive heart failure, (4) incidence of a three-point major adverse cardiovascular events composite (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke), (5) incidence of peripheral vascular disease, (6) change in urinary albumin-to-creatinine ratio from baseline to 6 months and (7) rate of annual change in estimated glomerular filtration rate (eGFR) during the study period.Ethics and disseminationThis study was approved by the VA Central Institutional Review Board (cIRB/18-36) and will be conducted in compliance with the Declaration of Helsinki and the Guidelines for Good Clinical Practice. The Hines Cooperative Studies Programme will finalise the study results, which will be published in accordance with the Consolidated Standards of Reporting Trials statement in a peer-reviewed scientific journal.Trial registration numberNCT03625648.

scholarly journals Interactions among Long Non-Coding RNAs and microRNAs Influence Disease Phenotype in Diabetes and Diabetic Kidney Disease

2021 ◽  
Vol 22 (11) ◽  
pp. 6027
Author(s):  
Swayam Prakash Srivastava ◽  
Julie E. Goodwin ◽  
Pratima Tripathi ◽  
Keizo Kanasaki ◽  
Daisuke Koya
Keyword(s):  
Kidney Disease ◽  
Large Scale ◽  
Diabetic Kidney Disease ◽  
Kidney Diseases ◽  
Noncoding Rnas ◽  
Therapeutic Targets ◽  
Disease Phenotype ◽  
Aberrant Expression ◽  
Diabetic Kidney ◽  
Health And Disease

Large-scale RNA sequencing and genome-wide profiling data revealed the identification of a heterogeneous group of noncoding RNAs, known as long noncoding RNAs (lncRNAs). These lncRNAs play central roles in health and disease processes in diabetes and cancer. The critical association between aberrant expression of lncRNAs in diabetes and diabetic kidney disease have been reported. LncRNAs regulate diverse targets and can function as sponges for regulatory microRNAs, which influence disease phenotype in the kidneys. Importantly, lncRNAs and microRNAs may regulate bidirectional or crosstalk mechanisms, which need to be further investigated. These studies offer the novel possibility that lncRNAs may be used as potential therapeutic targets for diabetes and diabetic kidney diseases. Here, we discuss the functions and mechanisms of actions of lncRNAs, and their crosstalk interactions with microRNAs, which provide insight and promise as therapeutic targets, emphasizing their role in the pathogenesis of diabetes and diabetic kidney disease

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