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Frontiers in Immunology 2023Diabetic nephropathy (DN) often leads to end-stage renal disease. Oxidative stress demonstrates a crucial act in the onset and progression of DN, which triggers various... (Review)
Review
Diabetic nephropathy (DN) often leads to end-stage renal disease. Oxidative stress demonstrates a crucial act in the onset and progression of DN, which triggers various pathological processes while promoting the activation of inflammation and forming a vicious oxidative stress-inflammation cycle that induces podocyte injury, extracellular matrix accumulation, glomerulosclerosis, epithelial-mesenchymal transition, renal tubular atrophy, and proteinuria. Conventional treatments for DN have limited efficacy. Polyphenols, as antioxidants, are widely used in DN with multiple targets and fewer adverse effects. This review reveals the oxidative stress and oxidative stress-associated inflammation in DN that led to pathological damage to renal cells, including podocytes, endothelial cells, mesangial cells, and renal tubular epithelial cells. It demonstrates the potent antioxidant and anti-inflammatory properties by targeting Nrf2, SIRT1, HMGB1, NF-κB, and NLRP3 of polyphenols, including quercetin, resveratrol, curcumin, and phenolic acid. However, there remains a long way to a comprehensive understanding of molecular mechanisms and applications for the clinical therapy of polyphenols.
Topics: Humans; Diabetic Nephropathies; Polyphenols; Endothelial Cells; Oxidative Stress; Antioxidants; Inflammation; Diabetes Mellitus
PubMed: 37545494
DOI: 10.3389/fimmu.2023.1185317 -
Journal of Translational Medicine Jul 2023Diabetic nephropathy (DN) is one of the serious microvascular complications of diabetes mellitus (DM). A growing body of research has demonstrated that the inflammatory...
BACKGROUND
Diabetic nephropathy (DN) is one of the serious microvascular complications of diabetes mellitus (DM). A growing body of research has demonstrated that the inflammatory state plays a critical role in the incidence and development of DN. Pyroptosis is a new way of programmed cell death, which has the particularity of natural immune inflammation. The inhibition of inflammatory cytokine expression and regulation of pathways related to pyroptosis may be a novel strategy for DN treatment. The aim of this study is to identify pyroptosis-related genes and potential drugs for DN.
METHODS
DN differentially expressed pyroptosis-related genes were identified via bioinformatic analysis Gene Expression Omnibus (GEO) dataset GSE96804. Dataset GSE30528 and GSE142025 were downloaded to verify pyroptosis-related differentially expressed genes (DEGs). Least absolute shrinkage and selection operator (LASSO) regression analysis was used to construct a pyroptosis-related gene predictive model. A consensus clustering analysis was performed to identify pyroptosis-related DN subtypes. Subsequently, Gene Set Variation Analysis (GSVA), Gene Ontology (GO) function enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted to explore the differences between DN clusters. A protein-protein interaction (PPI) network was used to select hub genes and DGIdb database was utilized to screen potential therapeutic drugs/compounds targeting hub genes.
RESULTS
A total of 24 differentially expressed pyroptosis-related genes were identified in DN. A 16 gene predictive model was conducted via LASSO regression analysis. According to the expression level of these 16 genes, DN cases were divided into two subtypes, and the subtypes are mainly associated with inflammation, activation of immune response and cell metabolism. In addition, we identified 10 hub genes among these subtypes, and predicted 65 potential DN therapeutics that target key genes.
CONCLUSION
We identified two pyroptosis-related DN clusters and 65 potential therapeutical agents/compounds for DN, which might shed a light on the treatment of DN.
Topics: Humans; Diabetic Nephropathies; Pyroptosis; Apoptosis; Cluster Analysis; Computational Biology; Inflammation; Diabetes Mellitus
PubMed: 37480090
DOI: 10.1186/s12967-023-04350-w -
Biomedicine & Pharmacotherapy =... Dec 2023Diabetic nephropathy (DN) is a severe complication of diabetes mellitus, posing significant challenges in terms of early prevention, clinical diagnosis, and treatment.... (Review)
Review
Diabetic nephropathy (DN) is a severe complication of diabetes mellitus, posing significant challenges in terms of early prevention, clinical diagnosis, and treatment. Consequently, it has emerged as a major contributor to end-stage renal disease. The glomerular filtration barrier, composed of podocytes, endothelial cells, and the glomerular basement membrane, plays a vital role in maintaining renal function. Disruptions in podocyte function, including hypertrophy, shedding, reduced density, and apoptosis, can impair the integrity of the glomerular filtration barrier, resulting in elevated proteinuria, abnormal glomerular filtration rate, and increased creatinine levels. Hence, recent research has increasingly focused on the role of podocyte injury in DN, with a growing emphasis on exploring therapeutic interventions targeting podocyte injury. Studies have revealed that factors such as lipotoxicity, hemodynamic abnormalities, oxidative stress, mitochondrial dysfunction, and impaired autophagy can contribute to podocyte injury. This review aims to summarize the underlying mechanisms of podocyte injury in DN and provide an overview of the current research status regarding experimental drugs targeting podocyte injury in DN. The findings presented herein may offer potential therapeutic targets and strategies for the management of DN associated with podocyte injury.
Topics: Humans; Podocytes; Diabetic Nephropathies; Endothelial Cells; Proteinuria; Kidney Failure, Chronic; Diabetes Mellitus
PubMed: 37837883
DOI: 10.1016/j.biopha.2023.115670 -
Frontiers in Endocrinology 2023Diabetic nephropathy (DN) and diabetic retinopathy (DR) are the most serious and common diabetes-associated complications. DN and DR are all highly prevalent and... (Review)
Review
Diabetic nephropathy (DN) and diabetic retinopathy (DR) are the most serious and common diabetes-associated complications. DN and DR are all highly prevalent and dangerous global diseases, but the underlying mechanism remains to be elucidated. Ferroptosis, a relatively recently described type of cell death, has been confirmed to be involved in the occurrence and development of various diabetic complications. The disturbance of cellular iron metabolism directly triggers ferroptosis, and abnormal iron metabolism is closely related to diabetes. However, the molecular mechanism underlying the role of ferroptosis in DN and DR is still unclear, and needs further study. In this review article, we summarize and evaluate the mechanism of ferroptosis and its role and progress in DN and DR, it provides new ideas for the diagnosis and treatment of DN and DR.
Topics: Humans; Diabetic Nephropathies; Ferroptosis; Retinal Diseases; Diabetic Retinopathy; Iron; Diabetes Mellitus
PubMed: 37600716
DOI: 10.3389/fendo.2023.1215292 -
Redox Biology Aug 2023Diabetic vascular complications can affect both microvascular and macrovascular. Diabetic microvascular complications, such as diabetic nephropathy, diabetic... (Review)
Review
Diabetic vascular complications can affect both microvascular and macrovascular. Diabetic microvascular complications, such as diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, and diabetic cardiomyopathy, are believed to be caused by oxidative stress. The Nox family of NADPH oxidases is a significant source of reactive oxygen species and plays a crucial role in regulating redox signaling, particularly in response to high glucose and diabetes mellitus. This review aims to provide an overview of the current knowledge about the role of Nox4 and its regulatory mechanisms in diabetic microangiopathies. Especially, the latest novel advances in the upregulation of Nox4 that aggravate various cell types within diabetic kidney disease will be highlighted. Interestingly, this review also presents the mechanisms by which Nox4 regulates diabetic microangiopathy from novel perspectives such as epigenetics. Besides, we emphasize Nox4 as a therapeutic target for treating microvascular complications of diabetes and summarize drugs, inhibitors, and dietary components targeting Nox4 as important therapeutic measures in preventing and treating diabetic microangiopathy. Additionally, this review also sums up the evidence related to Nox4 and diabetic macroangiopathy.
Topics: Humans; NADPH Oxidase 4; NADPH Oxidases; Reactive Oxygen Species; Oxidative Stress; Diabetic Nephropathies; Diabetic Angiopathies; Diabetes Mellitus
PubMed: 37321060
DOI: 10.1016/j.redox.2023.102781 -
Frontiers in Endocrinology 2023A causal relationship concerning coffee intake and diabetic nephropathy (DN) is controversial. We conducted a Mendelian randomization study to assess the causal nature...
RATIONALE AND OBJECTIVE
A causal relationship concerning coffee intake and diabetic nephropathy (DN) is controversial. We conducted a Mendelian randomization study to assess the causal nature of these associations.
METHODS
40 independent single nucleotide polymorphisms (SNPs) associated with coffee intake were selected from the UK Biobank study. Summary-level data for diabetic nephropathy were obtained from publicly available genome-wide association studies (GWAS) and the FinnGen consortium. Inverse variance weighted (IVW), MR-Egger, and weighted median (WM) methods were used to examine a causal association. Sensitivity analyses included Cochran's Q test, the intercept of MR-Egger, MR-PRESSO, and the Outlier method. Leave-One-Out sensitivity analyses were also conducted to reduce the heterogeneity.
RESULTS
Our current study demonstrated positive associations of genetically predicted coffee intake with diabetic nephropathy (OR=1.939; = 0.045 and type 2 diabetes with renal complications (OR = 2.787, = 0.047). These findings were robust across several sensitivity analyses.
CONCLUSIONS
This study found a positive correlation between coffee consumption and the risk of diabetic nephropathy using genetic data. For a more accurate and trustworthy conclusion, subgroup analysis on coffee intake, including preparing method, variety of coffee, and quantity, is required.
Topics: Humans; Diabetic Nephropathies; Coffee; Diabetes Mellitus, Type 2; Genome-Wide Association Study; Mendelian Randomization Analysis
PubMed: 37469984
DOI: 10.3389/fendo.2023.1169933 -
Diabetologia Sep 2023Diabetes is associated with excess morbidity and mortality due to both micro- and macrovascular complications, as well as a range of non-classical comorbidities.... (Review)
Review
Diabetes is associated with excess morbidity and mortality due to both micro- and macrovascular complications, as well as a range of non-classical comorbidities. Diabetes-associated microvascular complications are those considered most closely related to hyperglycaemia in a causal manner. However, some individuals with hyperglycaemia (even those with severe hyperglycaemia) do not develop microvascular diseases, which, together with evidence of co-occurrence of microvascular diseases in families, suggests a role for genetics. While genome-wide association studies (GWASs) produced firm evidence of multiple genetic variants underlying differential susceptibility to type 1 and type 2 diabetes, genetic determinants of microvascular complications are mostly suggestive. Identified susceptibility variants of diabetic kidney disease (DKD) in type 2 diabetes mirror variants underlying chronic kidney disease (CKD) in individuals without diabetes. As for retinopathy and neuropathy, reported risk variants currently lack large-scale replication. The reported associations between type 2 diabetes risk variants and microvascular complications may be explained by hyperglycaemia. More extensive phenotyping, along with adjustments for unmeasured confounding, including both early (fetal) and late-life (hyperglycaemia, hypertension, etc.) environmental factors, are urgently needed to understand the genetics of microvascular complications. Finally, genetic variants associated with reduced glycolysis, mitochondrial dysfunction and DNA damage and sustained cell regeneration may protect against microvascular complications, illustrating the utility of studies in individuals who have escaped these complications.
Topics: Humans; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Genome-Wide Association Study; Diabetic Nephropathies; Hyperglycemia; Risk Factors
PubMed: 37452207
DOI: 10.1007/s00125-023-05964-x -
Frontiers in Endocrinology 2023Diabetic kidney disease (DKD) is a chronic complication of diabetes and the leading cause of end-stage renal disease (ESRD) worldwide. Currently, there are limited... (Review)
Review
Diabetic kidney disease (DKD) is a chronic complication of diabetes and the leading cause of end-stage renal disease (ESRD) worldwide. Currently, there are limited therapeutic drugs available for DKD. While previous research has primarily focused on glomerular injury, recent studies have increasingly emphasized the role of renal tubular injury in the pathogenesis of DKD. Various factors, including hyperglycemia, lipid accumulation, oxidative stress, hypoxia, RAAS, ER stress, inflammation, EMT and programmed cell death, have been shown to induce renal tubular injury and contribute to the progression of DKD. Additionally, traditional hypoglycemic drugs, anti-inflammation therapies, anti-senescence therapies, mineralocorticoid receptor antagonists, and stem cell therapies have demonstrated their potential to alleviate renal tubular injury in DKD. This review will provide insights into the latest research on the mechanisms and treatments of renal tubular injury in DKD.
Topics: Humans; Diabetic Nephropathies; Kidney Failure, Chronic; Apoptosis; Hyperglycemia; Hypoglycemic Agents; Diabetes Mellitus
PubMed: 37600689
DOI: 10.3389/fendo.2023.1238927 -
International Journal of Biological... 2023Ferroptosis is an iron-dependent programmed cell death pattern that is characterized by iron overload, reactive oxygen species (ROS) accumulation and lipid peroxidation.... (Review)
Review
Ferroptosis is an iron-dependent programmed cell death pattern that is characterized by iron overload, reactive oxygen species (ROS) accumulation and lipid peroxidation. Growing viewpoints support that the imbalance of iron homeostasis and the disturbance of lipid metabolism contribute to tissue or organ injury in various kidney diseases by triggering ferroptosis. At present, the key regulators and complicated network mechanisms associated with ferroptosis have been deeply studied; however, its role in the initiation and progression of kidney diseases has not been fully revealed. Herein, we aim to discuss the features, key regulators and complicated network mechanisms associated with ferroptosis, explore the emerging roles of organelles in ferroptosis, gather its pharmacological progress, and systematically summarize the most recent discoveries about the crosstalk between ferroptosis and kidney diseases, including renal cell carcinoma (RCC), acute kidney injury (AKI), diabetic kidney disease (DKD), autosomal dominant polycystic kidney disease (ADPKD), renal fibrosis, lupus nephritis (LN) and IgA nephropathy. We further conclude the potential therapeutic strategies by targeting ferroptosis for the prevention and treatment of kidney diseases and hope that this work will provide insight for the further study of ferroptosis in the pathogenesis of kidney-related diseases.
Topics: Humans; Ferroptosis; Diabetic Nephropathies; Acute Kidney Injury; Kidney Neoplasms; Iron; Lipid Peroxidation
PubMed: 37564215
DOI: 10.7150/ijbs.85674 -
Biomedicine & Pharmacotherapy =... Aug 2023Diabetic nephropathy (DN) is characterized by tubulointerstitial fibrosis caused by epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells. Although...
Diabetic nephropathy (DN) is characterized by tubulointerstitial fibrosis caused by epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells. Although ferroptosis promotes DN development, the specific pathological process that is affected by ferroptosis in DN remains unclear. Herein, EMT-related changes, including increased α-smooth muscle actin (α-SMA) and Vimentin expression and decreased E-cadherin expression, were observed in the renal tissues of streptozotocin-induced DN mice and high glucose-cultured human renal proximal tubular (HK-2) cells. Treatment with ferrostatin-1 (Fer-1) ameliorated these changes and rescued renal pathological injury in diabetic mice. Interestingly, endoplasmic reticulum stress (ERS) was activated during EMT progression in DN. Inhibiting ERS improved the expression of EMT-associated indicators and further rescued the characteristic changes in ferroptosis caused by high glucose, including reactive oxygen species (ROS) accumulation, iron overload, increased lipid peroxidation product generation, and reduced mitochondrial cristae. Moreover, overexpression of XBP1 increased Hrd1 expression and inhibited NFE2-related factor 2 (Nrf2) expression, which could enhance cell susceptibility to ferroptosis. Co-immunoprecipitation (Co-IP) and ubiquitylation assays indicated that Hrd1 interacted with and ubiquitinated Nrf2 under high-glucose conditions. Collectively, our results demonstrated that ERS triggers ferroptosis-related EMT progression through the XBP1-Hrd1-Nrf2 pathway, which provides new insights into potential mechanisms for delaying EMT progression in DN.
Topics: Animals; Humans; Mice; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Endoplasmic Reticulum Stress; Epithelial-Mesenchymal Transition; Ferroptosis; Glucose; NF-E2-Related Factor 2; X-Box Binding Protein 1
PubMed: 37224754
DOI: 10.1016/j.biopha.2023.114897