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Proteomics. Clinical Applications Jun 2024Diabetic kidney disease (DKD) is a serious complication of diabetes mellitus and a leading cause of chronic kidney disease and end-stage renal disease. One potential...
PURPOSE
Diabetic kidney disease (DKD) is a serious complication of diabetes mellitus and a leading cause of chronic kidney disease and end-stage renal disease. One potential mechanism underlying cellular dysfunction contributing to kidney disease is aberrant protein post-translational modifications. Lysine acetylation is associated with cellular metabolic flux and is thought to be altered in patients with diabetes and dysfunctional renal metabolism.
EXPERIMENTAL DESIGN
A novel extraction and LC-MS/MS approach was adapted to quantify sites of lysine acetylation from formalin-fixed paraffin-embedded (FFPE) kidney tissue and from patients with DKD and non-diabetic donors (n = 5 and n = 7, respectively).
RESULTS
Analysis of FFPE tissues identified 840 total proteins, with 225 of those significantly changing in patients with DKD. Acetylomic analysis quantified 289 acetylated peptides, with 69 of those significantly changing. Pathways impacted in DKD patients revealed numerous metabolic pathways, specifically mitochondrial function, oxidative phosphorylation, and sirtuin signaling. Differential protein acetylation in DKD patients impacted sirtuin signaling, valine, leucine, and isoleucine degradation, lactate metabolism, oxidative phosphorylation, and ketogenesis.
CONCLUSIONS AND CLINICAL RELEVANCE
A quantitative acetylomics platform was developed for protein biomarker discovery in formalin-fixed and paraffin-embedded biopsies of kidney transplant patients suffering from DKD.
PubMed: 38923810
DOI: 10.1002/prca.202400018 -
Current Diabetes Reviews Jun 2024Diabetic nephropathy (DN), the primary risk factor for end-stage kidney disease (ESKD) that requires dialysis or renal transplantation, affects up to 50% of individuals...
BACKGROUND
Diabetic nephropathy (DN), the primary risk factor for end-stage kidney disease (ESKD) that requires dialysis or renal transplantation, affects up to 50% of individuals with diabetes.
OBJECTIVE
In this article, potential mechanisms, biomarkers, and possible therapeutic targets will be discussed, as well as their interventional therapies.
METHODS
A literature review was done from databases like Google Scholar, PUBMEDMEDLINE, and Scopus using standard keywords "Diabetic Nephropathy," "Biomarkers," "Pathophysiology," "Cellular Mechanism," "Cell Therapy," "Treatment Therapies" from 2010- 2023. It has been studied that metabolic as well as hemodynamic pathways resulting from hyperglycemia act as mediators for renal disease.
RESULTS
We identified 270 articles, of which 210 were reviewed in full-text and 90 met the inclusion criteria. Every therapy regimen for the prevention and treatment of DN must include the blocking of ANG-II action. By reducing inflammatory and fibrotic markers brought on by hyperglycemia, an innovative approach to halting the progression of diabetic mellitus (DN) involves combining sodium-glucose cotransporter-2 inhibitors with renin-angiotensin-aldosterone system blockers. When compared to taking either medicine alone, this method works better. AGEs, protein kinase C (PKC), and the renin-angiotensin aldosterone system (RAAS) are among the components that are inhibited in DN management strategies.
CONCLUSION
Thus, it can be concluded that the multifactorial condition of DN needs to be treated at an early stage. Novel therapies with a combination of cell therapies and diet management are proven to be effective in the management of DN.
PubMed: 38919001
DOI: 10.2174/0115733998291920240611063402 -
Hong Kong Medical Journal = Xianggang... Jun 2024
PubMed: 38918067
DOI: 10.12809/hkmj245162 -
Pharmacological Research Jun 2024The longevity protein sirtuins (SIRTs) belong to a family of nicotinamide adenine dinucleotide (NAD)-dependent deacetylases. In mammals, SIRTs comprise seven members... (Review)
Review
The longevity protein sirtuins (SIRTs) belong to a family of nicotinamide adenine dinucleotide (NAD)-dependent deacetylases. In mammals, SIRTs comprise seven members (SIRT1-7) which are localized to different subcellular compartments. As the most prominent mitochondrial deacetylases, SIRT3 is known to be regulated by various mechanisms and participate in virtually all aspects of mitochondrial homeostasis and metabolism, exerting significant impact on multiple organs. Notably, the kidneys possess an abundance of mitochondria that provide substantial energy for filtration and reabsorption. A growing body of evidence now supports the involvement of SIRT3 in several renal diseases, including acute kidney injury, chronic kidney disease, and diabetic nephropathy; notably, these diseases are all associated with aging. In this review, we summarize the emerging role of SIRT3 in renal diseases and aging, and highlights the intricate mechanisms by which SIRT3 exerts its effects. In addition, we highlight the potential therapeutic significance of modulating SIRT3 and provide valuable insights into the therapeutic role of SIRT3 in renal diseases to facilitate clinical application.
PubMed: 38917912
DOI: 10.1016/j.phrs.2024.107261 -
Aging and Disease May 2024Type 2 diabetes (T2D) is a widespread health condition both in the United States and around the world, with insulin resistance playing a critical role in its...
Type 2 diabetes (T2D) is a widespread health condition both in the United States and around the world, with insulin resistance playing a critical role in its development. Effective treatment strategies are essential for managing T2D and mitigating associated risks. Adiponectin (APN), secreted by adipocytes, exhibits an inverse correlation with obesity-related adiposity, and its levels are negatively associated with insulin resistance and body mass index. This study aimed to enhance endogenous APN levels in a diet-induced obese (DIO) mouse model using lipid nanoparticles (LNP) as safe delivery agents for APN mRNA conjugates. The results indicate that APN-mRNA-LNP administration successfully induced APN synthesis in various tissues, including muscle, liver, kidney, pancreas, and adipose cells. This induction was associated with several positive outcomes, such as preventing diet-induced body weight gain, improving hyperglycemia by promoting Glut-4 expression, alleviating diabetic nephropathy symptoms by blocking the EGFR pathway, and reducing pro-inflammatory cytokine production. In addition, the treatment demonstrated enhanced insulin sensitivity by activating DGKd and inhibiting PKCε. This resulted in reactivation of insulin receptors in insulin target tissues and stimulation of insulin secretion from pancreatic beta cells. The findings of the present study highlight the potential of APN-mRNA-LNP-based nucleic acid therapy as a treatment for type 2 diabetes, offering a comprehensive approach to addressing its complexities.
PubMed: 38916734
DOI: 10.14336/AD.2024.0162 -
Frontiers in Endocrinology 2024The co-occurrence of kidney disease in patients with type 2 diabetes (T2D) is a major public health challenge. Although early detection and intervention can prevent or...
OBJECTIVE
The co-occurrence of kidney disease in patients with type 2 diabetes (T2D) is a major public health challenge. Although early detection and intervention can prevent or slow down the progression, the commonly used estimated glomerular filtration rate (eGFR) based on serum creatinine may be influenced by factors unrelated to kidney function. Therefore, there is a need to identify novel biomarkers that can more accurately assess renal function in T2D patients. In this study, we employed an interpretable machine-learning framework to identify plasma metabolomic features associated with GFR in T2D patients.
METHODS
We retrieved 1626 patients with type 2 diabetes (T2D) in Liaoning Medical University First Affiliated Hospital (LMUFAH) as a development cohort and 716 T2D patients in Second Affiliated Hospital of Dalian Medical University (SAHDMU) as an external validation cohort. The metabolite features were screened by the orthogonal partial least squares discriminant analysis (OPLS-DA). We compared machine learning prediction methods, including logistic regression (LR), support vector machine (SVM), random forest (RF), and eXtreme Gradient Boosting (XGBoost). The Shapley Additive exPlanations (SHAP) were used to explain the optimal model.
RESULTS
For T2D patients, compared with the normal or elevated eGFR group, glutarylcarnitine (C5DC) and decanoylcarnitine (C10) were significantly elevated in GFR mild reduction group, and citrulline and 9 acylcarnitines were also elevated significantly (FDR<0.05, FC > 1.2 and VIP > 1) in moderate or severe reduction group. The XGBoost model with metabolites had the best performance: in the internal validate dataset (AUROC=0.90, AUPRC=0.65, BS=0.064) and external validate cohort (AUROC=0.970, AUPRC=0.857, BS=0.046). Through the SHAP method, we found that C5DC higher than 0.1μmol/L, Cit higher than 26 μmol/L, triglyceride higher than 2 mmol/L, age greater than 65 years old, and duration of T2D more than 10 years were associated with reduced GFR.
CONCLUSION
Elevated plasma levels of citrulline and a panel of acylcarnitines were associated with reduced GFR in T2D patients, independent of other conventional risk factors.
Topics: Humans; Diabetes Mellitus, Type 2; Glomerular Filtration Rate; Machine Learning; Male; Female; Middle Aged; Aged; Biomarkers; Metabolomics; Carnitine; Cohort Studies; Diabetic Nephropathies
PubMed: 38915893
DOI: 10.3389/fendo.2024.1279034 -
JCI Insight Jun 2024Our previous study identified 8 risk and 9 protective plasma miRNAs associated with progression to end-stage kidney disease (ESKD) in diabetes. This study aimed to...
Our previous study identified 8 risk and 9 protective plasma miRNAs associated with progression to end-stage kidney disease (ESKD) in diabetes. This study aimed to elucidate preanalytical factors that influence the quantification of circulating miRNAs. Using the EdgeSeq platform, which quantifies 2,002 miRNAs in plasma, including ESKD-associated miRNAs, we compared miRNA profiles in whole plasma versus miRNA profiles in RNA extracted from the same plasma specimens. Less than half of the miRNAs were detected in standard RNA extraction from plasma. Detection of individual and concentrations of miRNAs were much lower when RNA extracted from plasma was quantified by RNA sequencing (RNA-Seq) or quantitative reverse transcription PCR (qRT-PCR) platforms compared with EdgeSeq. Plasma profiles of miRNAs determined by the EdgeSeq platform had excellent reproducibility in assessment and had no variation with age, sex, hemoglobin A1c, BMI, and cryostorage time. The risk ESKD-associated miRNAs were detected and measured accurately only in whole plasma and using the EdgeSeq platform. Protective ESKD-associated miRNAs were detected by all platforms except qRT-PCR; however, correlations among concentrations obtained with different platforms were weak or nonexistent. In conclusion, preanalytical factors have a profound effect on detection and quantification of circulating miRNAs in ESKD in diabetes. Quantification of miRNAs in whole plasma and using the EdgeSeq platform may be the preferable method to study profiles of circulating cell-free miRNAs associated with ESKD and possibly other diseases.
Topics: Humans; Circulating MicroRNA; Kidney Failure, Chronic; Male; Female; Middle Aged; Diabetic Nephropathies; Biomarkers; Aged; Reproducibility of Results; Adult; MicroRNAs; Disease Progression; Diabetes Mellitus
PubMed: 38912578
DOI: 10.1172/jci.insight.174153 -
Current Pharmaceutical Design Jun 2024Diabetic nephropathy is one of the main causes of kidney failure in the end stage of diabetes worldwide. On the other hand, asafoetida is a gum whose hypoglycemic...
OBJECTIVE
Diabetic nephropathy is one of the main causes of kidney failure in the end stage of diabetes worldwide. On the other hand, asafoetida is a gum whose hypoglycemic effects have been proven. The present study was conducted with the aim of using asafoetida to prevent diabetic nephropathy.
METHODS
Diabetes was induced by a high-fat diet (60%) and streptozotocin injection (35 mg/kg) in rats. Diabetic rats were treated with an oral dose of 50 mg/kg of asafoetida for 8 weeks. At the end of the experiment, serum and urine parameters were examined. Antioxidant enzymes and lipid peroxidation levels in the kidney were also determined along with its histological examination. The expression levels of tumor necrosis factor-alpha and Transforming growth factor beta genes were also evaluated.
RESULTS
Glucose, cholesterol, triglyceride, and HbA1c concentrations were significantly reduced in the asafoetida 50. On the other hand, in the treatment group, serum creatinine, urea, and albumin levels decreased and increased in urine. Antioxidant enzymes in the kidney improved significantly, and the expression of tumour necrosis factor-alpha and transforming growth factor-beta genes decreased. Histopathological examination also showed that necrosis, epithelial damage, and leukocyte infiltration increased in the diabetic and the treatment group.
CONCLUSION
The result of biochemical analysis, enzymatic, and histological examinations showed that asafoetida may delay the progression of diabetic nephropathy due to the presence of anti-inflammatory and antioxidant activities.
PubMed: 38910415
DOI: 10.2174/0113816128303631240530045628 -
Cell Death & Disease Jun 2024Diabetic kidney disease, known as a glomerular disease, arises from a metabolic disorder impairing renal cell function. Mitochondria, crucial organelles, play a key role... (Review)
Review
Diabetic kidney disease, known as a glomerular disease, arises from a metabolic disorder impairing renal cell function. Mitochondria, crucial organelles, play a key role in substance metabolism via oxidative phosphorylation to generate ATP. Cells undergo metabolic reprogramming as a compensatory mechanism to fulfill energy needs for survival and growth, attracting scholarly attention in recent years. Studies indicate that mitochondrial metabolic reprogramming significantly influences the pathophysiological progression of DKD. Alterations in kidney metabolism lead to abnormal expression of signaling molecules and activation of pathways, inducing oxidative stress-related cellular damage, inflammatory responses, apoptosis, and autophagy irregularities, culminating in renal fibrosis and insufficiency. This review delves into the impact of mitochondrial metabolic reprogramming on DKD pathogenesis, emphasizing the regulation of metabolic regulators and downstream signaling pathways. Therapeutic interventions targeting renal metabolic reprogramming can potentially delay DKD progression. The findings underscore the importance of focusing on metabolic reprogramming to develop safer and more effective therapeutic approaches.
Topics: Humans; Diabetic Nephropathies; Mitochondria; Animals; Signal Transduction; Oxidative Stress; Kidney; Metabolic Reprogramming
PubMed: 38910210
DOI: 10.1038/s41419-024-06833-0 -
Journal of Controlled Release :... Jun 2024Diabetic nephropathy is a severe complication of diabetes. Treatment of diabetic nephropathy is an important challenge due to persistent hyperglycemia and elevated...
Diabetic nephropathy is a severe complication of diabetes. Treatment of diabetic nephropathy is an important challenge due to persistent hyperglycemia and elevated levels of reactive oxygen species (ROS) in the kidney. Herein, we designed a glycopolymersome that can treat type 2 diabetic nephropathy by effectively inhibiting hyperglycemia and ROS-associated diabetic nephropathy pathogenesis. The glycopolymersome is self-assembled from phenylboronic acid derivative-containing copolymer, poly(ethylene oxide)-block-poly[(aspartic acid)-stat-glucosamine-stat-(phenylboronic acid)-stat-(phenylboronic acid pinacol ester)] [PEO-b-P(Asp-stat-GA-stat-PBA-stat-PAPE)]. PBA segment can reversibly bind blood glucose or GA segment for long-term regulation of blood glucose levels; PAPE segment can scavenge excessive ROS for renoprotection. In vitro studies confirmed that the glycopolymersomes exhibit efficient blood glucose responsiveness within 2 h and satisfactory ROS-scavenging ability with 500 μM HO. Moreover, the glycopolymersomes display long-acting regulation of blood glucose levels in type 2 diabetic nephropathy mice within 32 h. Dihydroethidium staining revealed that these glycopolymersomes reduced ROS to normal levels in the kidney, which led to 61.7% and 76.6% reduction in creatinine and urea levels, respectively, along with suppressing renal apoptosis, collagen accumulation, and glycogen deposition in type 2 diabetic nephropathy mice. Notably, the polypeptide-based glycopolymersome was synthesized by ring-opening polymerization (ROP) of N-carboxyanhydrides (NCAs), thereby exhibiting favorable biodegradability. Overall, we proposed a new glycopolymersome strategy for 'drug-free' treatment of diabetic nephropathy, which could be extended to encompass the design of various multifunctional nanoparticles targeting diabetes and its associated complications.
PubMed: 38908757
DOI: 10.1016/j.jconrel.2024.06.049